Amide derivatives of N-urea substituted amino acids as formyl peptide receptor like-1 (FPRL-1) receptor modulators

ABSTRACT

The present invention relates to novel amide derivatives of N-urea substituted amino acids, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of the N-formyl peptide receptor like-1 (FPRL-1) receptor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/949,335, filed Apr. 10, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/408,643, filed Jan. 18, 2017, now U.S. Pat. No.9,974,772, issued May 22, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/138,823, filed Apr. 26, 2016, now U.S. Pat. No.9,579,307, issued on Feb. 28, 2017, which is a continuation of U.S.patent application Ser. No. 14/608,503, filed Jan. 29, 2015, now U.S.Pat. No. 9,351,948, issued May 31, 2016, which is a continuation of U.S.patent application Ser. No. 14/102,145, filed Dec. 10, 2013, now U.S.Pat. No. 8,993,780, issued Mar. 31, 2015, which is a divisional of U.S.patent application Ser. No. 13/658,523, filed Oct. 23, 2012, now U.S.Pat. No. 8,658,803, issued Feb. 25, 2014, which claims the benefit ofpriority to U.S. Provisional Application Ser. No. 61/551,772, filed Oct.26, 2011, each of which are hereby incorporated by reference in theirentireties, and serve as the basis for a priority and/or benefit claimof the present application.

FIELD OF THE INVENTION

The present invention relates to novel amide derivatives of N-ureasubstituted amino acids, processes for preparing them, pharmaceuticalcompositions containing them and their use as pharmaceuticals asmodulators of the N-formyl peptide receptor like-1 (FPRL-1) receptor.The invention relates specifically to the use of these compounds andtheir pharmaceutical compositions to treat disorders associated with theN-formyl peptide receptor like-1 (FPRL-1) receptor modulation.

BACKGROUND OF THE INVENTION

The N-formyl peptide receptor like-1 (FPRL-1) receptor is a Gprotein-coupled receptor that is expressed on inflammatory cells such asmonocytes and neutrophils, as well as T cells and has been shown to playa critical role in leukocyte trafficking during inflammation and humanpathology. FPRL-1 is an exceptionally promiscuous receptor that respondsto a large array of exogenous and endogenous ligands, including Serumamyloid A (SAA), chemokine variant sCKβ8-1, the neuroprotective peptidehuman, anti-inflammatory eicosanoid lipoxin A4 (LXA4) andglucocorticoid-modulated protein annexin A1. FPRL-1 transducesanti-inflammatory effects of LXA4 in many systems, but it also canmediate the pro-inflammatory signaling cascade of peptides such as SAA.The ability of the receptor to mediate two opposite effects is proposedto be a result of different receptor domains used by different agonists(Parmentier, Marc et al. Cytokine & Growth Factor Reviews 17 (2006)501-519).

Activation of FPRL-1 by LXA4 or its analogs and by Annexin I protein hasbeen shown to result in anti-inflammatory activity by promoting activeresolution of inflammation which involves inhibition ofpolymorphonuclear neutrophil (PMN) and eosinophil migration and alsostimulate monocyte migration enabling clearance of apoptotic cells fromthe site of inflammation in a nonphlogistic manner. In addition, FPRL-1has been shown to inhibit natural killer (NK) cell cytotoxicity andpromote activation of T cells which further contributes to downregulation of tissue damaging inflammatory signals. FPRL-1/LXA4interaction has been shown to be beneficial in experimental models ofischemia reperfusion, angiogenesis, dermal inflammation,chemotherapy-induced alopecia, ocular inflammation such asendotoxin-induced uveitis, corneal wound healing, re-epithelializationetc. FPRL-1 thus represents an important novel pro-resolutionarymolecular target for the development of new therapeutic agents indiseases with excessive inflammatory responses.

JP 06172288 discloses the preparation of phenylalanine derivatives ofgeneral formula:

as inhibitors of acyl-coenzyme A:cholesterol acyltransferase derivativesuseful for the treatment of arteriosclerosis-related various diseasessuch as angina pectoris, cardiac infarction, temporary ischemic spasm,peripheral thrombosis or obstruction.

Journal of Combinatorial Chemistry (2007), 9(3), 370-385 teaches athymidinyl dipeptide urea library with structural similarity to thenucleoside peptide class of antibiotics:

WO 9965932 discloses tetrapeptides or analogs or peptidomimetics thatselectively bind mammalian opioid receptors:

Helvetica Chimica Acta (1998), 81(7), 1254-1263 teaches the synthesisand spectroscopic characterization of 4-chlorophenyl isocyanate(1-chloro-4-isocyanatobenzene) adducts with amino acids as potentialdosimeters for the biomonitoring of isocyanate exposure:

EP 457195 discloses the preparation of peptides having endothelinantagonist activity and pharmaceutical compositions comprising them:

Yingyong Huaxue (1990), 7(1), 1-9 teaches the structure-activityrelations of di- and tripeptide sweeteners and of L-phenyl alaninederivatives:

FR 2533210 discloses L-phenyl alanine derivatives as syntheticsweeteners:

WO2005047899 discloses compounds which selectively activate the FPRL-1receptor represented by the following scaffolds:

SUMMARY OF THE INVENTION

A group of amide derivatives of N-urea substituted amino acids, whichare potent and selective FPRL-1 modulators, has been discovered. Assuch, the compounds described herein are useful in treating a widevariety of disorders associated with modulation of FPRL-1 receptor. Theterm “modulator” as used herein, includes but is not limited to:receptor agonist, antagonist, inverse agonist, inverse antagonist,partial agonist, and partial antagonist.

This invention describes compounds of Formula I, which have FPRL-1receptor biological activity. The compounds in accordance with thepresent invention are thus of use in medicine, for example in thetreatment of humans with diseases and conditions that are alleviated byFPRL-1 modulation.

In one aspect, the invention provides a compound represented by FormulaI or the individual geometrical isomers, individual enantiomers,individual diastereoisomers, individual tautomers, individualzwitterions or a pharmaceutically acceptable salt thereof:

wherein:a is 0 or 1;b is 0, 1, 2, 3 or 4;R¹ is optionally substituted C₁₋₈ alkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted heterocycle, optionally substitutedC₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl, optionallysubstituted C₃₋₈ cycloalkenyl, —NH₂, —OH, —O(C₁₋₈ alkyl),R² is optionally substituted C₁₋₈ alkyl, optionally substituted C₆₋₁₀aryl,R³ is H, optionally substituted C₁₋₈ alkyl, halogen, —COOH, —OH, —NH₂,NO₂, optionally substituted heterocycle, optionally substituted C₃₋₈cycloalkyl, optionally substituted C₆₋₁₀ aryl, optionally substitutedC₃₋₈ cycloalkenyl;R⁴ is H, optionally substituted C₁₋₈ alkyl, halogen, —COOH, —OH, —NH₂,—NO₂, optionally substituted heterocycle, optionally substituted C₃₋₈cycloalkyl, optionally substituted C₆₋₁₀ aryl, optionally substitutedC₃₋₈ cycloalkenyl;R⁵ is optionally substituted C₁₋₈ alkyl, halogen, —COOH, —OH, —NH₂,—NO₂, optionally substituted heterocycle, optionally substituted C₃₋₈cycloalkyl, optionally substituted C₆₋₁₀ aryl, optionally substitutedC₃₋₈ cycloalkenyl;R⁶ is H, optionally substituted C₁₋₈ alkyl, halogen, —COOH, —OH, —NH₂,—NO₂, optionally substituted heterocycle, optionally substituted C₃₋₈cycloalkyl, optionally substituted C₆₋₁₀ aryl, optionally substitutedC₃₋₈ cycloalkenyl;R⁷ is H, optionally substituted C₁₋₈ alkyl, halogen, —COOH, —OH, —NH₂,—NO₂, optionally substituted heterocycle, optionally substituted C₃₋₈cycloalkyl, optionally substituted C₆₋₁₀ aryl, optionally substitutedC₃₋₈ cycloalkenyl;and compounds:

In another aspect, the invention provides a compound represented byFormula II or the geometrical isomers, enantiomers, diastereoisomers,tautomers, zwitterions, hydrates, crystal forms, solvates or apharmaceutically acceptable salt thereof:

wherein:a is 1 and b is 0;a is 0 and b is 1;a is 1 and b is 1;R¹ is optionally substituted C₁₋₈ alkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted heterocycle, optionally substitutedC₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl, optionallysubstituted C₃₋₈ cycloalkenyl, —NR¹¹R¹² or —OR¹³;R² is optionally substituted C₁₋₈ alkyl or optionally substituted C₆₋₁₀aryl;R³ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁴ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁵ is halogen, —CF₃ or S(O)_(n)R¹⁴;n is 0, 1 or 2;R⁶ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁷ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁸ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R⁹ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R¹⁰ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R^(9a) is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R^(10a) is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R¹¹ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹² is hydrogen or optionally substituted C₁₋₈ alkyl;R¹³ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹⁴ is hydrogen, CF₃ or optionally substituted C₁₋₈ alkyl;R¹⁵ is hydrogen or optionally substituted C₁₋₈ alkyl;with the provisos:a). when a=1 and b=0 then:

R⁹ is not optionally substituted benzyl; and

R¹¹ is not:

and

the compound of Formula II is not of structures:

andb). when a=0 and b=1 then:

R¹ is OR¹³; and

the compound of Formula II is not of structure:

andc). when a=1 and b=1 then:

R¹¹ is not:

In another aspect, the invention provides a compound represented byFormula II,wherein:a is 1 and b is 0;R¹ is optionally substituted C₁₋₈ alkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted heterocycle, optionally substitutedC₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl, optionallysubstituted C₃₋₈ cycloalkenyl, —NR¹¹R¹² or —OR¹³;R² is optionally substituted C₁₋₈ alkyl or optionally substituted C₆₋₁₀aryl;R³ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁴ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁵ is halogen, —CF₃ or S(O)_(n)R¹⁴;n is 0, 1 or 2;R⁶ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁷ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁸ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R⁹ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R¹⁰ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R¹¹ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹² is hydrogen or optionally substituted C₁₋₈ alkyl;R¹³ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹⁴ is hydrogen, CF₃ or optionally substituted C₁₋₈ alkyl;R¹⁵ is hydrogen or optionally substituted C₁₋₈ alkyl;with the provisos:

R⁹ is not optionally substituted benzyl; and

R¹¹ is not:

and

the compound of Formula II is not of structures:

In another aspect, the invention provides a compound represented byFormula II,wherein:a is 1 and b is 0;R¹ is optionally substituted C₁₋₈ alkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted heterocycle, optionally substitutedC₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl, optionallysubstituted C₃₋₈ cycloalkenyl, —NR¹¹R¹² or —OR¹³;R² is optionally substituted C₁₋₈ alkyl or optionally substituted C₆₋₁₀aryl;R³ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁴ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁵ is S(O)_(n)R¹⁴;n is 0, 1 or 2;R⁶ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁷ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁸ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R⁹ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R¹⁰ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R¹¹ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹² is hydrogen or optionally substituted C₁₋₈ alkyl;R¹³ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹⁴ is hydrogen, CF₃ or optionally substituted C₁₋₈ alkyl;R¹⁵ is hydrogen or optionally substituted C₁₋₈ alkyl;with the provisos:

R⁹ is not optionally substituted benzyl; and

R¹¹ is not:

and

the compound of Formula II is not of structures:

In another aspect, the invention provides a compound represented byFormula II,wherein:a is 1 and b is 0;R¹ is optionally substituted C₁₋₈ alkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted heterocycle, optionally substitutedC₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl, optionallysubstituted C₃₋₈ cycloalkenyl, —NR¹¹R¹² or —OR¹³;R² is optionally substituted C₁₋₈ alkyl or optionally substituted C₆₋₁₀aryl;R³ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁴ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁵ is —CF₃;R⁶ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁷ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁸ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R⁹ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R¹⁰ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R¹¹ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹² is hydrogen or optionally substituted C₁₋₈ alkyl;R¹³ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹⁵ is hydrogen or optionally substituted C₁₋₈ alkyl;with the provisos:

R⁹ is not optionally substituted benzyl; and

R¹¹ is not:

and

the compound of Formula II is not of structures:

In another aspect, the invention provides a compound represented byFormula II, wherein:a is 1 and b is 0;R¹ is optionally substituted C₁₋₈ alkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted heterocycle, optionally substitutedC₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl, optionallysubstituted C₃₋₈ cycloalkenyl, —NR¹¹R¹² or —OR¹³;R² is optionally substituted C₁₋₈ alkyl or optionally substituted C₆₋₁₀aryl;R³ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁴ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁵ is halogen;R⁶ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁷ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁸ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R⁹ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R¹⁰ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R¹¹ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹² is hydrogen or optionally substituted C₁₋₈ alkyl;R¹³ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹⁵ is hydrogen or optionally substituted C₁₋₈ alkyl;with the provisos:

R⁹ is not optionally substituted benzyl;

and the compound of Formula II is not of structures:

and

R¹¹ is not:

In another aspect, the invention provides a compound represented byFormula II,whereina is 1 and b is 0;R¹ is optionally substituted C₁₋₈ alkyl, —NR¹¹R¹² or —OR¹³;R² is optionally substituted C₁₋₈ alkyl;R³ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹²;R⁴ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹²;R⁵ is halogen, —CF₃ or S(O)_(n)R¹⁴;n is 0, 1 or 2;R⁶ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹²;R⁷ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹²;R⁸ is hydrogen or optionally substituted C₁₋₈ alkyl;R⁹ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R¹⁰ is hydrogen or optionally substituted C₁₋₈;R¹¹ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹² is hydrogen or optionally substituted C₁₋₈ alkyl;R¹³ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹⁴ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹⁵ is hydrogen or optionally substituted C₁₋₈ alkyl;with the provisos:R⁹ is not optionally substituted benzyl;and the compound of Formula II is not of structures:

andR¹¹ is not:

In another aspect, the invention provides a compound represented byFormula II,whereina is 1 and b is 0;R¹ is optionally substituted C₁₋₈ alkyl, —NR¹¹R¹² or —OR¹³;R² is optionally substituted C₁₋₈ alkyl;R³ is hydrogen or halogen;R⁴ is hydrogen;R⁵ is halogen, —CF₃ or S(O)_(n)R¹⁴;n is 0, 1 or 2;R⁶ is hydrogen;R⁷ is hydrogen;R⁸ is hydrogen, optionally substituted C₁₋₈ alkyl;R⁹ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R¹⁰ is hydrogen, optionally substituted C₁₋₈ alkyl;R¹¹ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹² is hydrogen or optionally substituted C₁₋₈ alkyl;R¹³ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹⁴ is hydrogen or optionally substituted C₁₋₈ alkyl;with the provisos:R⁹ is not optionally substituted benzyl;and the compound of Formula II is not of structures:

andR¹¹ is not:

In another aspect, the invention provides a compound represented byFormula II,whereina is 0 and b is 1;R¹ is —OR¹³;R² is optionally substituted C₁₋₈ alkyl or optionally substituted C₆₋₁₀aryl;R³ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁴ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁵ is halogen, —CF₃ or S(O)_(n)R¹⁴;n is 0, 1 or 2;R⁶ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁷ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁸ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R⁹ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R¹⁹ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R^(9a) is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R^(10a) is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R¹¹ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹² is hydrogen or optionally substituted C₁₋₈ alkyl;R¹³ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹⁴ is hydrogen, CF₃ or optionally substituted C₁₋₈ alkyl;R¹⁵ is hydrogen or optionally substituted C₁₋₈ alkyl; andthe compound of Formula II is not of structure:

In another aspect, the invention provides a compound represented byFormula II,

wherein

a is 0 and b is 1;

R¹ is —OR¹³;

R² is optionally substituted C₁₋₈ alkyl or optionally substituted C₆₋₁₀aryl;

R³ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;

R⁴ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;

R⁵ is halogen;

R⁶ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;

R⁷ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;

R⁸ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R⁹ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R¹⁰ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R^(9a) is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R^(10a) is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R¹¹ is hydrogen or optionally substituted C₁₋₈ alkyl;

R¹² is hydrogen or optionally substituted C₁₋₈ alkyl;

R¹³ is hydrogen or optionally substituted C₁₋₈ alkyl;

R¹⁵ is hydrogen or optionally substituted C₁₋₈ alkyl; and

the compound of Formula II is not of structure:

In another aspect, the invention provides a compound represented byFormula II,wherein:a is 0 and b is 1;R¹ is —OR¹³;R² is optionally substituted C₁₋₈ alkyl;R³ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen;R⁴ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen;R⁵ is halogen, —CF₃ or S(O)_(n)R¹⁴;n is 0, 1 or 2;R⁶ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen;R⁷ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen;R⁸ is hydrogen;R⁹ is hydrogen;R¹⁰ is hydrogen, optionally substituted C₁₋₈ alkyl;R^(9a) is hydrogen, optionally substituted C₁₋₈ alkyl;R^(10a) is hydrogen, optionally substituted C₁₋₈ alkyl;R¹³ is hydrogen or optionally substituted C₁₋₈ alkyl; andR¹⁴ is hydrogen, CF₃ or optionally substituted C₁₋₈ alkyl; andthe compound of Formula II is not of structure:

In another aspect, the invention provides a compound represented byFormula II,wherein:a is 0 and b is 1;R¹ is —OR¹³;R² is optionally substituted C₁₋₈ alkyl;R³ is hydrogen or halogen;R⁴ is hydrogen;R⁵ is halogen;R⁶ is hydrogen;R⁷ is hydrogen;R⁸ is hydrogen;R⁹ is hydrogen;R¹⁰ is hydrogen or optionally substituted C₁₋₈ alkyl;R^(9a) is hydrogen or optionally substituted C₁₋₈ alkyl;R^(10a) is hydrogen or optionally substituted C₁₋₈ alkyl; andR¹³ is hydrogen; andthe compound of Formula II is not of structure:

In another aspect, the invention provides a compound represented byFormula II,wherein:a is 0 and b is 1;R¹ is —OR¹³;R² is optionally substituted C₁₋₈ alkyl;R³ is hydrogen or halogen;R⁴ is hydrogen;R⁵ is halogen;R⁶ is hydrogen;R⁷ is hydrogen;R⁸ is hydrogen;R⁹ is hydrogen;R¹⁰ is hydrogen or optionally substituted C₁₋₈ alkyl;R^(9a) is optionally substituted C₁₋₈ alkyl;R^(10a) is optionally substituted C₁₋₈ alkyl; andR¹³ is hydrogen.

In another aspect, the invention provides a compound represented byFormula II,

wherein

a is 1 and b is 1;

R¹ is optionally substituted C₁₋₈ alkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted heterocycle, optionally substitutedC₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl, optionallysubstituted C₃₋₈ cycloalkenyl, —NR¹¹R¹² or —OR¹³;

R² is optionally substituted C₁₋₈ alkyl or optionally substituted C₆₋₁₀aryl;

R³ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;

R⁴ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;

R⁵ is halogen, —CF₃ or S(O)_(n)R¹⁴;

n is 0, 1 or 2;

R⁶ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;

R⁷ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;

R⁸ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R⁹ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R¹⁹ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R^(9a) is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R^(10a) is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R¹¹ is hydrogen or optionally substituted C₁₋₈ alkyl;

R¹² is hydrogen or optionally substituted C₁₋₈ alkyl;

R¹³ is hydrogen or optionally substituted C₁₋₈ alkyl;

R¹⁴ is hydrogen or optionally substituted C₁₋₈ alkyl; and

R¹⁵ is hydrogen or optionally substituted C₁₋₈ alkyl; and

with the proviso:

that R¹¹ is not:

In another aspect, the invention provides a compound represented byFormula II,

wherein

a is 1 and b is 1;

R¹ is optionally substituted C₁₋₈ alkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted heterocycle, optionally substitutedC₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl, optionallysubstituted C₃₋₈ cycloalkenyl, —NR¹¹R¹² or —OR¹³;

R² is optionally substituted C₁₋₈ alkyl or optionally substituted C₆₋₁₀aryl;

R³ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;

R⁴ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;

R⁵ is halogen;

R⁶ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;

R⁷ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;

R⁸ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R⁹ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R¹⁰ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R^(9a) is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R^(10a) is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;

R¹¹ is hydrogen or optionally substituted C₁₋₈ alkyl;

R¹² is hydrogen or optionally substituted C₁₋₈ alkyl;

R¹³ is hydrogen or optionally substituted C₁₋₈ alkyl;

R¹⁵ is hydrogen or optionally substituted C₁₋₈ alkyl; and

with the proviso:

that R¹¹ is not:

In another aspect, the invention provides a compound represented byFormula II,

wherein

a is 1 and b is 1;

R¹ is optionally substituted C₁₋₈ alkyl, —NR¹¹R¹² or —OR¹³;

R² is optionally substituted C₁₋₈ alkyl or optionally substituted C₆₋₁₀aryl;

R³ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen;

R⁴ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen;

R⁵ is halogen, —CF₃ or S(O)_(n)R¹⁴;

n is 0, 1 or 2;

R⁶ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen;

R⁷ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen;

R⁸ is hydrogen;

R⁹ is hydrogen, optionally substituted C₁₋₈ alkyl;

R¹⁰ is hydrogen, optionally substituted C₁₋₈ alkyl;

R^(9a) is hydrogen, optionally substituted C₁₋₈ alkyl;

R^(10a) is hydrogen, optionally substituted C₁₋₈ alkyl;

R¹¹ is hydrogen or optionally substituted C₁₋₈ alkyl;

R¹² is hydrogen or optionally substituted C₁₋₈ alkyl;

R¹³ is hydrogen or optionally substituted C₁₋₈ alkyl;

R¹⁴ is hydrogen or optionally substituted C₁₋₈ alkyl; and

R¹⁵ is hydrogen or optionally substituted C₁₋₈ alkyl;

with the proviso:

that R¹¹ is not:

In another aspect, the invention provides a compound represented byFormula II,whereina is 1 and b is 1;R¹ is —OR¹³;R² is optionally substituted C₁₋₈ alkyl or optionally substituted C₆₋₁₀aryl;R³ is hydrogen;R⁴ is hydrogen;R⁵ is halogen;R⁶ is hydrogen;R⁷ is hydrogen;R⁸ is hydrogen;R⁹ is hydrogen;R¹⁰ is hydrogen;R^(9a) is hydrogen;R^(10a) is hydrogen; andR¹³ is hydrogen or optionally substituted C₁₋₈ alkyl; andwith the proviso:that R¹¹ is not:

The term “alkyl”, as used herein, refers to saturated, monovalent ordivalent hydrocarbon moieties having linear or branched moieties orcombinations thereof and containing 1 to 8 carbon atoms. One methylene(—CH₂—) group, of the alkyl group can be replaced by oxygen, sulfur,sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate,amide, sulfonamide, by a divalent C₃₋₈ cycloalkyl, by a divalentheterocycle, or by a divalent aryl group. Alkyl groups can have one ormore chiral centers. Alkyl groups can be independently substituted byhalogen atoms, hydroxyl groups, cycloalkyl groups, amino groups,heterocyclic groups, aryl groups, carboxylic acid groups, phosphonicacid groups, sulphonic acid groups, phosphoric acid groups, nitrogroups, amide groups, sulfonamide groups.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms derived from a saturated cyclichydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic.Cycloalkyl can be independently substituted by halogen atoms, sulfonylC₁₋₈ alkyl groups, sulfoxide C₁₋₈ alkyl groups, sulfonamide groups,nitro groups, cyano groups, —OC₁₋₈ alkyl groups, —SC₁₋₈ alkyl groups,—C₁₋₈ alkyl groups, —C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups, ketonegroups, alkylamino groups, amino groups, aryl groups, C₃₋₈ cycloalkylgroups or hydroxyl groups.

The term “cycloalkenyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms derived from a saturatedcycloalkyl having at least one double bond. Cycloalkenyl groups can bemonocyclic or polycyclic. Cycloalkenyl groups can be independentlysubstituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitrogroups, cyano groups, —OC₁₋₆ alkyl groups, —SC₁₋₆ alkyl groups, —C₁₋₆alkyl groups, —C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups, ketone groups,alkylamino groups, amino groups, aryl groups, C₃₋₈ cycloalkyl groups orhydroxyl groups.

The term “halogen”, as used herein, refers to an atom of chlorine,bromine, fluorine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one double bond. One methylene (—CH₂—) group, ofthe alkenyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen,carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, bya divalent C₃₋₈ cycloalkyl, by a divalent heterocycle, or by a divalentaryl group. C₂₋₆ alkenyl can be in the E or Z configuration. Alkenylgroups can be substituted by alkyl groups, as defined above or byhalogen atoms.

The term “alkynyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one triple bond. One methylene (—CH₂—) group, ofthe alkynyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen,carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, bya divalent C₃₋₈ cycloalkyl, by a divalent heterocycle, or by a divalentaryl group. Alkynyl groups can be substituted by alkyl groups, asdefined above, or by halogen atoms.

The term “heterocycle” as used herein, refers to a 3 to 10 memberedring, which can be aromatic or non-aromatic, saturated or unsaturated,containing at least one heteroatom selected form oxygen, nitrogen,sulfur, or combinations of at least two thereof, interrupting thecarbocyclic ring structure. The heterocyclic ring can be interrupted bya C═O; the S and N heteroatoms can be oxidized. Heterocycles can bemonocyclic or polycyclic. Heterocyclic ring moieties can be substitutedby halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyanogroups, —OC₁₋₆ alkyl groups, —SC₁₋₆ alkyl groups, —C₁₋₈ alkyl groups,—C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups, ketone groups, alkylaminogroups, amino groups, aryl groups, C₃₋₈ cycloalkyl groups or hydroxylgroups.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms, by removal of one hydrogen atom. Aryl can be substituted byhalogen atoms, sulfonyl C₁₋₆ alkyl groups, sulfoxide C₁₋₆ alkyl groups,sulfonamide groups, carboxylic acid groups, C₁₋₆ alkyl carboxylates(ester) groups, amide groups, nitro groups, cyano groups, —OC₁₋₆ alkylgroups, —SC₁₋₆ alkyl groups, —C₁₋₆ alkyl groups, —C₂₋₆ alkenyl groups,—C₂₋₆ alkynyl groups, ketone groups, aldehydes, alkylamino groups, aminogroups, aryl groups, C₃₋₈ cycloalkyl groups or hydroxyl groups. Arylscan be monocyclic or polycyclic.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “carbonyl” as used herein, represents a group of formula“—C(O)—”.

The term “ketone” as used herein, represents an organic compound havinga carbonyl group linked to a carbon atom such as —(CO)R^(x) whereinR^(x) can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle asdefined above.

The term “amine” as used herein, represents a group of formula“—NR^(x)R^(y)”, wherein R^(x) and R^(y) can be the same or independentlyH, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

The term “carboxyl” as used herein, represents a group of formula“—C(O)O—”.

The term “sulfonyl” as used herein, represents a group of formula “—SO₂⁻”.

The term “sulfate” as used herein, represents a group of formula“—O—S(O)₂—O—”.

The term “sulfonate” as used herein, represents a group of the formula“—S(O)₂—O—”.

The term “carboxylic acid” as used herein, represents a group of formula“—C(O)OH”.

The term “nitro” as used herein, represents a group of formula “NO₂”.

The term “cyano” as used herein, represents a group of formula “—CN”.

The term “amide” as used herein, represents a group of formula“—C(O)NR^(x)R^(y),” wherein R^(x) and R^(y) can be the same orindependently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle asdefined above.

The term “sulfonamide” as used herein, represents a group of formula“—S(O)₂NR^(x)R^(y)” wherein R^(x) and R^(y) can be the same orindependently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle asdefined above.

The term “sulfoxide” as used herein, represents a group of formula“—S(O)—”.

The term “phosphonic acid” as used herein, represents a group of formula“—P(O)(OH)₂”.

The term “phosphoric acid” as used herein, represents a group of formula“—OP(O)(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula“—S(O)₂OH”.

The formula “H”, as used herein, represents a hydrogen atom.

The formula “O”, as used herein, represents an oxygen atom.

The formula “N”, as used herein, represents a nitrogen atom.

The formula “S”, as used herein, represents a sulfur atom.

The invention discloses compounds

-   {[2-{[(4-bromophenyl)carbamoyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}acetic    acid;-   tert-butyl    {[2-{[(4-bromophenyl)carbamoyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}acetate;-   [(4-amino-2-{[(4-bromophenyl)carbamoyl]amino}-4-oxobutanoyl)amino]acetic    acid;-   tert-butyl    [(4-amino-2-{[(4-bromophenyl)carbamoyl]amino}-4-oxobutanoyl)amino]acetate;-   2-{[(2R)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-2-methylpropanoic    acid;-   tert-butyl    2-{[(2R)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-2-methylpropanoate;-   {[2-{[(4-bromophenyl)carbamoyl]amino}-3-(1H-imidazol-4-yl)propanoyl]amino}acetic    acid;-   tert-butyl    {[2-{[(4-bromophenyl)carbamoyl]amino}-3-(1H-imidazol-4-yl)propanoyl]amino}acetate;-   {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-(methylsulfonyl)butanoyl]amino}acetic    acid;-   tert-butyl    {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-(methylsulfonyl)butanoyl]amino}acetate;-   {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-(methylsulfanyl)butanoyl]amino}acetic    acid;-   tert-butyl    {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-(methylsulfanyl)butanoyl]amino}acetate;-   2-methyl-2-{[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}propanoic    acid;-   tert-butyl    2-methyl-2-{[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}propanoate;-   {[(2S)-4-methyl-2-({[4-(methylsulfonyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic    acid;-   tert-butyl    {[(2S)-4-methyl-2-({[4-(methylsulfonyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate;-   {[(2S)-4-methyl-2-({[4-(methylsulfinyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic    acid;-   tert-butyl    {[(2S)-4-methyl-2-({[4-(methylsulfinyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate;-   2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-2-methylpropanoic    acid;-   tert-butyl    2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-2-methylpropanoate;-   ({(2S)-4-methyl-2-[({4-[(trifluoromethyl)sulfanyl]phenyl}carbamoyl)amino]pentanoyl}amino)acetic    acid;-   tert-butyl    ({(2S)-4-methyl-2-[({4-[(trifluoromethyl)sulfanyl]phenyl}carbamoyl)amino]pentanoyl}amino)acetate;-   {[(2S)-4-methyl-2-({[4-(methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic    acid;-   tert-butyl    {[(2S)-4-methyl-2-({[4-(methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate;-   {[(2R)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic    acid;-   tert-butyl    {[(2R)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetate;-   {[(2R,3R)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetic    acid;-   tert-butyl    {[(2R,3R)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetate;-   {[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic    acid;-   tert-butyl    {[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate;-   {[(2R)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic    acid;-   (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-[2-(dimethylamino)-2-oxoethyl]-4-methylpentanamide;-   [(2-{[(4-bromophenyl)carbamoyl]amino}-2-methylpropanoyl)amino]acetic    acid;-   tert-butyl    [(2-{[(4-bromophenyl)carbamoyl]amino}-2-methylpropanoyl)amino]acetate;-   [(2-{[(4-bromophenyl)carbamoyl]amino}-2-ethylbutanoyl)amino]acetic    acid;-   tert-butyl    [(2-{[(4-bromophenyl)carbamoyl]amino}-2-ethylbutanoyl)amino]acetate;-   [(2-{[(4-bromophenyl)carbamoyl]amino}-2,4-dimethylpentanoyl)amino]acetic    acid;-   tert-butyl    [(2-{[(4-bromophenyl)carbamoyl]amino}-2,4-dimethylpentanoyl)amino]acetate;-   (2S)—N-[(1S)-2-amino-2-oxo-1-phenylethyl]-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanamide;-   (2S)—{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}(phenyl)ethanoic    acid;-   tert-butyl    (2S)—{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}(phenyl)ethanoate;-   (2S)—N-[(2S)-1-amino-1-oxopentan-2-yl]-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanamide;-   (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}pentanoic    acid;-   tert-butyl    (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}pentanoate;-   (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-[(2R)-1-hydroxypropan-2-yl]-4-methylpentanamide;-   (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2,3-dihydroxypropyl)-4-methylpentanamide;-   (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(1,3-dihydroxypropan-2-yl)-4-methylpentanamide;-   (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxy-2-methylpropyl)-4-methylpentanamide;-   (2S)—N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanamide;-   (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-3-methylbutanoic    acid;-   tert-butyl    (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-3-methylbutanoate;-   (2S)—N-[(2S)-1-amino-1-oxopropan-2-yl]-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanamide;-   (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}propanoic    acid;-   tert-butyl    (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}propanoate;-   (2S)—N-[(2S)-1-amino-1-oxopropan-2-yl]-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanamide;-   (2S)-2-{[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}propanoic    acid;-   tert-butyl    (2S)-2-{[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}propanoate;-   (2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-4-methylpentanamide;-   (2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methyl-N-(2-oxopropyl)pentanamide;-   (2S)—N-(2-amino-2-oxoethyl)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanamide;-   {[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic    acid;-   tert-butyl    {([2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetate;-   (2S)—N-(2-amino-2-oxoethyl)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}pentanamide;-   (2S)—N-(2-amino-2-oxoethyl)-2-{[(4-bromophenyl)carbamoyl]amino}pentanamide;-   (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methyl-N-(2-oxopropyl)pentanamide;-   (2S)—N-(2-amino-2-oxoethyl)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanamide;-   {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic    acid;-   (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxy    ethyl)-4-methylpentanamide;-   tert-butyl    {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetate;-   {([2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}pentanoyl]amino}acetic    acid;-   tert-butyl    {[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}pentanoyl]amino}acetate;-   (2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N-(2-oxopropyl)pentanamide;-   (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-oxopropyl)pentanamide;-   propan-2-yl    {([2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate;-   ethyl    {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate;-   methyl    {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate;-   (2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)pentanamide;-   (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)pentanamide;-   (2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-3-phenylpropanamide;-   {([2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetic    acid;-   tert-butyl    {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate;-   (2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N-(2-oxopropyl)-3-phenylpropanamide;-   (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-oxopropyl)-3-phenylpropanamide;-   (2S,3S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-3-methylpentanamide;-   (2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-3-methylpentanamide;-   (2S,3S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-3-methyl-N-(2-oxopropyl)pentanamide;-   (2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methyl-N-(2-oxopropyl)pentanamide;-   (2S,3S)—N-(2-amino-2-oxoethyl)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-3-methylpentanamide;-   (2S,3S)—N-(2-amino-2-oxoethyl)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanamide;-   {[(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetic    acid;-   tert-butyl    {[(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetate;-   {([2S,3S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetic    acid;-   tert-butyl    {[(2S,3S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetate;-   (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-3-phenylpropanamide;-   3-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino}propanoic    acid;-   tert-butyl    3-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino}propanoate;-   {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino}acetic    acid;-   tert-butyl    {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino}acetate.-   In another aspect the invention discloses compounds:-   {[2-{[(4-bromophenyl)carbamoyl]amino}-3-(1H-imidazol-4-yl)propanoyl]amino}acetic    acid;-   tert-butyl    {[2-{[(4-bromophenyl)carbamoyl]amino}-3-(1H-imidazol-4-yl)propanoyl]amino}acetate;-   {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-(methylsulfonyl)butanoyl]amino}acetic    acid;-   tert-butyl    {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-(methylsulfonyl)butanoyl]amino}acetate;-   {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-(methylsulfanyl)butanoyl]amino}acetic    acid;-   tert-butyl    {[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-(methylsulfanyl)butanoyl]amino}acetate;-   2-methyl-2-{[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}propanoic    acid;-   tert-butyl    2-methyl-2-{[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}propanoate;-   {[(2S)-4-methyl-2-({[4-(methylsulfonyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic    acid;-   tert-butyl    {[(2S)-4-methyl-2-({[4-(methylsulfonyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate;-   {[(2S)-4-methyl-2-({[4-(methylsulfinyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic    acid;-   tert-butyl    {[(2S)-4-methyl-2-({[4-(methylsulfinyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate;-   2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-2-methylpropanoic    acid;-   tert-butyl    2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-2-methylpropanoate;-   ({(2S)-4-methyl-2-[({4-[(trifluoromethyl)sulfanyl]phenyl}carbamoyl)amino]pentanoyl}amino)acetic    acid;-   tert-butyl    ({(2S)-4-methyl-2-[({4-[(trifluoromethyl)sulfanyl]phenyl}carbamoyl)amino]pentanoyl}amino)acetate;-   {[(2S)-4-methyl-2-({[4-(methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic    acid;-   tert-butyl    {[(2S)-4-methyl-2-({[4-(methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate;-   {[(2R)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic    acid;-   tert-butyl    {[(2R)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetate;-   {[(2R,3R)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetic    acid;-   tert-butyl    {[(2R,3R)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}acetate;-   {[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetic    acid;-   tert-butyl    {[(2S)-4-methyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]amino}acetate;-   (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-[2-(dimethylamino)-2-oxoethyl]-4-methylpentanamide;-   [(2-{[(4-bromophenyl)carbamoyl]amino}-2-methylpropanoyl)amino]acetic    acid;-   tert-butyl    [(2-{[(4-bromophenyl)carbamoyl]amino}-2-methylpropanoyl)amino]acetate;-   [(2-{[(4-bromophenyl)carbamoyl]amino}-2-ethylbutanoyl)amino]acetic    acid;-   tert-butyl    [(2-{[(4-bromophenyl)carbamoyl]amino}-2-ethylbutanoyl)amino]acetate;-   [(2-{[(4-bromophenyl)carbamoyl]amino}-2,4-dimethylpentanoyl)amino]acetic    acid;-   tert-butyl    [(2-{[(4-bromophenyl)carbamoyl]amino}-2,4-dimethylpentanoyl)amino]acetate;-   (2S)—N-[(1S)-2-amino-2-oxo-1-phenylethyl]-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanamide;-   (2S)—{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}(phenyl)ethanoic    acid;-   tert-butyl    (2S)—{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}(phenyl)ethanoate;-   (2S)—N-[(2S)-1-amino-1-oxopentan-2-yl]-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanamide;-   (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}pentanoic    acid;-   tert-butyl    (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}pentanoate;-   (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-[(2R)-1-hydroxypropan-2-yl]-4-methylpentanamide;-   (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2,3-dihydroxypropyl)-4-methylpentanamide;-   (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(1,3-dihydroxypropan-2-yl)-4-methylpentanamide;-   (2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2-hydroxy-2-methylpropyl)-4-methylpentanamide;-   (2S)—N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanamide;-   (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-3-methylbutanoic    acid;-   tert-butyl    (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-3-methylbutanoate;-   (2S)—N-[(2S)-1-amino-1-oxopropan-2-yl]-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanamide;-   (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}propanoic    acid;-   tert-butyl    (2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}propanoate;-   (2S)—N-[(2S)-1-amino-1-oxopropan-2-yl]-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanamide;-   (2S)-2-{[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}propanoic    acid;-   tert-butyl    (2S)-2-{[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}propanoate;-   (2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-4-methylpentanamide;-   (2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methyl-N-(2-oxopropyl)pentanamide;-   (2S)—N-(2-amino-2-oxoethyl)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanamide;-   {[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetic    acid;-   tert-butyl    {[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}acetate;-   tert-butyl    2-{[(2R)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-2-methylpropanoate;-   2-{[(2R)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-2-methylpropanoic    acid;-   tert-butyl    [(4-amino-2-{[(4-bromophenyl)carbamoyl]amino}-4-oxobutanoyl)amino]acetate;-   [(4-amino-2-{[(4-bromophenyl)carbamoyl]amino}-4-oxobutanoyl)amino]acetic    acid;-   tert-butyl    {[2-{[(4-bromophenyl)carbamoyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}acetate;-   {[2-{[(4-bromophenyl)carbamoyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}acetic    acid.

Some compounds of Formula I and of Formula II and some of theirintermediates have at least one asymmetric center in their structure.This asymmetric center may be present in an R or S configuration, said Rand S notation is used in correspondence with the rules described inPure Appli. Chem. (1976), 45, 11-13.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I and of Formula II are able toform.

The acid addition salt form of a compound of Formula I and of Formula IIthat occurs in its free form as a base can be obtained by treating thefree base with an appropriate acid such as an inorganic acid, forexample, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoricacid, nitric acid and the like; or an organic acid such as for example,acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvicacid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaricacid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannicacid, pamoic acid, citric acid, methylsulfonic acid, ethanesulfonicacid, benzenesulfonic acid, formic and the like (Handbook ofPharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds),Verlag Helvetica Chemica Acta-Zürich, 2002, 329-345).

The base addition salt form of a compound of Formula I and of Formula IIthat occurs in its acid form can be obtained by treating the acid withan appropriate base such as an inorganic base, for example, sodiumhydroxide, magnesium hydroxide, potassium hydroxide, Calcium hydroxide,ammonia and the like; or an organic base such as for example,L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like.(Handbook of Pharmaceutical Salts, P. Heinrich Stahal& Camille G.Wermuth (Eds), Verlag Helvetica Chemica Acta-Zürich, 2002, 329-345).

Compounds of Formula I and of Formula II and their salts can be in theform of a solvate, which is included within the scope of the presentinvention. Such solvates include for example hydrates, alcoholates andthe like.

With respect to the present invention reference to a compound orcompounds, is intended to encompass that compound in each of itspossible isomeric forms and mixtures thereof unless the particularisomeric form is referred to specifically.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

The compounds of the invention are indicated for use in treating orpreventing conditions in which there is likely to be a componentinvolving the N-formyl peptide receptor like-1 receptor.

In another embodiment, there are provided pharmaceutical compositionsincluding at least one compound of the invention in a pharmaceuticallyacceptable carrier.

In a further embodiment of the invention, there are provided methods fortreating disorders associated with modulation of the N-formyl peptidereceptor like-1 receptor.

Such methods can be performed, for example, by administering to asubject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one compound of theinvention.

Therapeutic utilities of the N-formyl peptide receptor like-1 receptormodulators are ocular inflammatory diseases including, but not limitedto, wet and dry age-related macular degeneration (ARMD), uveitis, dryeye, Keratitis, allergic eye disease and conditions affecting theposterior part of the eye, such as maculopathies and retinaldegeneration including non-exudative age related macular degeneration,exudative age related macular degeneration, choroidalneovascularization, diabetic retinopathy (proliferative), retinopathy ofprematurity (ROP), acute macular neuroretinopathy, central serouschorioretinopathy, cystoid macular edema, and diabetic macular edema;infectious keratitis, uveitis, herpetic keratitis, corneal angiogenesis,lymphangiogenesis, uveitis, retinitis, and choroiditis such as acutemultifocal placoid pigment epitheliopathy, Behcet's disease, birdshotretinochoroidopathy, infectious (syphilis, lyme, tuberculosis,toxoplasmosis), intermediate uveitis (pars planitis), multifocalchoroiditis, multiple evanescent white dot syndrome (mewds), ocularsarcoidosis, posterior scleritis, serpiginous choroiditis, subretinalfibrosis and uveitis syndrome, Vogt-Koyanagi- and Harada syndrome;vascular diseases/exudative diseases such as retinal arterial occlusivedisease, central retinal vein occlusion, cystoids macular edema,disseminated intravascular coagulopathy, branch retinal vein occlusion,hypertensive fundus changes, ocular ischemic syndrome, retinal arterialmicroaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinalvein occlusion, papillophlebitis, central retinal artery occlusion,branch retinal artery occlusion, carotid artery disease (CAD), frostedbranch angiitis, sickle cell retinopathy and other hemoglobinopathies,angioid streaks, familial exudative vitreoretinopathy, and Ealesdisease; traumatic/surgical conditions such as sympathetic ophthalmia,uveitic retinal disease, retinal detachment, trauma, post surgicalcorneal wound healing, conditions caused by laser, conditions caused byphotodynamic therapy, photocoagulation, hypoperfusion during surgery,radiation retinopathy, and bone marrow transplant retinopathy;proliferative disorders such as proliferative vitreal retinopathy andepiretinal membranes, and proliferative diabetic retinopathy; infectiousdisorders such as ocular histoplasmosis, ocular toxocariasis, presumedocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis,retinal diseases associated with HIV infection, choroidal diseaseassociate with HIV infection, uveitic disease associate with HIVinfection, viral retinitis, acute retinal necrosis, progressive outerretinal necrosis, fungal retinal diseases, ocular syphilis, oculartuberculosis, diffuse unilateral subacute neuroretinitis, and myiasis;genetic disorders such as retinitis pigmentosa, systemic disorders withaccosiated retinal dystrophies, congenital stationary night blindness,cone dystrophies, Stargardt's disease and fundus flavimaculatus, Best'sdisease, pattern dystrophy of the retinal pigmented epithelium, X-linkedretinoschisis, Sorsby's fundus dystrophy, benign concentric maculopathy,Bietti's crystalline dystrophy, and pseudoxanthoma elasticum; retinaltears/holes such as retinal detachment, macular hole, and giant retinaltear; tumors such as retinal disease associated with tumors, congenitalhypertrophy of the retinal pigmented epithelium, posterior uvealmelanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis,combined hamartoma of the retina and retinal pigmented epithelium,retinoblastoma, vasoproliferative tumors of the ocular fundus, retinalastrocytoma, and intraocular lymphoid tumors; and miscellaneous otherdiseases affecting the posterior part of the eye such as punctate innerchoroidopathy, acute posterior multifocal placoid pigmentepitheliopathy, myopic retinal degeneration, and acute retinal pigementepitheliitis, systemic inflammatory diseases such as stroke, coronaryartery disease, obstructive airway diseases, HIV-mediated retroviralinfections, cardiovascular disorders including coronary artery disease,neuroinflammation, neurological disorders, pain and immunologicaldisorders, asthma, allergic disorders, inflammation, systemic lupuserythematosus, psoriasis, CNS disorders such as Alzheimer's disease,arthritis, sepsis, inflammatory bowel disease, cachexia, anginapectoris, post-surgical corneal inflammation, blepharitis, MGD, dermalwound healing, burns, rosacea, atopic dermatitis, acne, psoriasis,seborrheic dermatitis, actinic keratoses, viral warts, photoaging,rheumatoid arthritis and related inflammatory disorders, alopecia,glaucoma, branch vein occlusion, Best's vitelliform maculardegeneration, retinitis pigmentosa, proliferative vitreoretinopathy(PVR), and any other degenerative disease of either the photoreceptorsor the RPE (Perretti, Mauro et al. Pharmacology & Therapeutics 127(2010) 175-188.)

These compounds are useful for the treatment of mammals, includinghumans, with a range of conditions and diseases that are alleviated bythe N-formyl peptide receptor like-1 receptor modulation: including, butnot limited to the treatment of wet and dry age-related maculardegeneration (ARMD), diabetic retinopathy (proliferative), retinopathyof prematurity (ROP), diabetic macular edema, uveitis, retinal veinocclusion, cystoids macular edema, glaucoma, branch vein occlusion,Best's vitelliform macular degeneration, retinitis pigmentosa,proliferative vitreoretinopathy (PVR), and any other degenerativedisease of either the photoreceptors or the RPE.In still another embodiment of the invention, there are provided methodsfor treating disorders associated with modulation of the FPRL-1receptor. Such methods can be performed, for example, by administeringto a subject in need thereof a therapeutically effective amount of atleast one compound of the invention, or any combination thereof, orpharmaceutically acceptable salts, hydrates, solvates, crystal forms andindividual isomers, enantiomers, and diastereomers thereof.

The present invention concerns the use of a compound of Formula I and ofFormula II or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for the treatment of ocular inflammatorydiseases including, but not limited to, wet and dry age-related maculardegeneration (ARMD), uveitis, dry eye, Keratitis, allergic eye diseaseand conditions affecting the posterior part of the eye, such asmaculopathies and retinal degeneration including non-exudative agerelated macular degeneration, exudative age related maculardegeneration, choroidal neovascularization, diabetic retinopathy(proliferative), retinopathy of prematurity (ROP), acute macularneuroretinopathy, central serous chorioretinopathy, cystoid macularedema, and diabetic macular edema; infectious keratitis, uveitis,herpetic keratitis, corneal angiogenesis, lymphangiogenesis, uveitis,retinitis, and choroiditis such as acute multifocal placoid pigmentepitheliopathy, Behcet's disease, birdshot retinochoroidopathy,infectious (syphilis, lyme, tuberculosis, toxoplasmosis), intermediateuveitis (pars planitis), multifocal choroiditis, multiple evanescentwhite dot syndrome (mewds), ocular sarcoidosis, posterior scleritis,serpiginous choroiditis, subretinal fibrosis and uveitis syndrome,Vogt-Koyanagi- and Harada syndrome; vascular diseases/exudative diseasessuch as retinal arterial occlusive disease, central retinal veinocclusion, cystoids macular edema, disseminated intravascularcoagulopathy, branch retinal vein occlusion, hypertensive funduschanges, ocular ischemic syndrome, retinal arterial microaneurysms,Coat's disease, parafoveal telangiectasis, hemi-retinal vein occlusion,papillophlebitis, central retinal artery occlusion, branch retinalartery occlusion, carotid artery disease (CAD), frosted branch angiitis,sickle cell retinopathy and other hemoglobinopathies, angioid streaks,familial exudative vitreoretinopathy, and Eales disease;traumatic/surgical conditions such as sympathetic ophthalmia, uveiticretinal disease, retinal detachment, trauma, post surgical corneal woundhealing, conditions caused by laser, conditions caused by photodynamictherapy, photocoagulation, hypoperfusion during surgery, radiationretinopathy, and bone marrow transplant retinopathy; proliferativedisorders such as proliferative vitreal retinopathy and epiretinalmembranes, and proliferative diabetic retinopathy; infectious disorderssuch as ocular histoplasmosis, ocular toxocariasis, presumed ocularhistoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, retinaldiseases associated with HIV infection, choroidal disease associate withHIV infection, uveitic disease associate with HIV infection, viralretinitis, acute retinal necrosis, progressive outer retinal necrosis,fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuseunilateral subacute neuroretinitis, and myiasis; genetic disorders suchas retinitis pigmentosa, systemic disorders with accosiated retinaldystrophies, congenital stationary night blindness, cone dystrophies,Stargardt's disease and fundus flavimaculatus, Best's disease, patterndystrophy of the retinal pigmented epithelium, X-linked retinoschisis,Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti'scrystalline dystrophy, and pseudoxanthoma elasticum; retinal tears/holessuch as retinal detachment, macular hole, and giant retinal tear; tumorssuch as retinal disease associated with tumors, congenital hypertrophyof the retinal pigmented epithelium, posterior uveal melanoma, choroidalhemangioma, choroidal osteoma, choroidal metastasis, combined hamartomaof the retina and retinal pigmented epithelium, retinoblastoma,vasoproliferative tumors of the ocular fundus, retinal astrocytoma, andintraocular lymphoid tumors; and miscellaneous other diseases affectingthe posterior part of the eye such as punctate inner choroidopathy,acute posterior multifocal placoid pigment epitheliopathy, myopicretinal degeneration, and acute retinal pigement epitheliitis, systemicinflammatory diseases such as stroke, coronary artery disease,obstructive airway diseases, HIV-mediated retroviral infections,cardiovascular disorders including coronary artery disease,neuroinflammation, neurological disorders, pain and immunologicaldisorders, asthma, allergic disorders, inflammation, systemic lupuserythematosus, psoriasis, CNS disorders such as Alzheimer's disease,arthritis, sepsis, inflammatory bowel disease, cachexia, anginapectoris, post-surgical corneal inflammation, blepharitis, MGD, dermalwound healing, burns, rosacea, atopic dermatitis, acne, psoriasis,seborrheic dermatitis, actinic keratoses, viral warts, photoaging,rheumatoid arthritis and related inflammatory disorders, alopecia,glaucoma, branch vein occlusion, Best's vitelliform maculardegeneration, retinitis pigmentosa, proliferative vitreoretinopathy(PVR), and any other degenerative disease of either the photoreceptorsor the RPE.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back to the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventioncompounds are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or diseasecondition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

The compounds of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein areuseful as medicaments in mammals, including humans, for treatment ofdiseases and/or alleviations of conditions which are responsive totreatment by agonists or functional antagonists of the N-formyl peptidereceptor like-1 (FPRL-1) receptor. Thus, in further embodiments of theinvention, there are provided methods for treating a disorder associatedwith modulation of the N-formyl peptide receptor like-1 (FPRL-1)receptor. Such methods can be performed, for example, by administeringto a subject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one invention compound. Asused herein, the term “therapeutically effective amount” means theamount of the pharmaceutical composition that will elicit the biologicalor medical response of a subject in need thereof that is being sought bythe researcher, veterinarian, medical doctor or other clinician. In someembodiments, the subject in need thereof is a mammal. In someembodiments, the mammal is human.

The present invention concerns also processes for preparing thecompounds of Formula I. The compounds of formula I according to theinvention can be prepared analogously to conventional methods asunderstood by the person skilled in the art of synthetic organicchemistry. Synthetic Scheme 1 set forth below, illustrates how thecompounds according to the invention can be made.

Compounds of Formula I were prepared as depicted in Scheme 1. Compoundsof Formula II were prepared as depicted in Scheme 2. In general, at-butyl ester derivative of an amino acid is reacted with a substitutedphenylisocyanate to produce a phenylurea derivative. The t-butyl esterprotecting group is then removed under acidic conditions to give theamino acid urea. The carboxylic acid group is then converted to an amideby treating the compound with activating reagents, such as1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) andHydroxybenzotriazole (HOBt) in the presence of an amine, or by othermethods known to those skilled in the art. At this stage, those skilledin the art will appreciate that many additional compounds that fallunder the scope of the invention may be prepared by performing variouscommon chemical reactions. Details of certain specific chemicaltransformations are provided in the examples.

Those skilled in the art will be able to routinely modify and/or adaptthe following scheme to synthesize any compounds of the inventioncovered by Formula I or Formula II.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand racemic mixtures. Some of the compounds of the invention may formsalts with pharmaceutically acceptable acids or bases, and suchpharmaceutically acceptable salts of the compounds described herein arealso within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of hydrogen ^(1H) (orH) or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

As will be evident to those skilled in the art, individual isomericforms can be obtained by separation of mixtures thereof in conventionalmanner. For example, in the case of diastereoisomeric isomers,chromatographic separation may be employed.

Compound names were generated with ACD version 12.5. In general,characterization of the compounds is performed according to thefollowing methods, NMR spectra are recorded on 300 or 600 MHz Varian andacquired at room temperature. Chemical shifts are given in ppmreferenced either to internal TMS or to the solvent signal.

All the reagents, solvents, catalysts for which the synthesis is notdescribed are purchased from chemical vendors such as Sigma Aldrich,Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, TransWorld Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth,Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex,MIC-scientific, Ltd; however some known intermediates, were preparedaccording to published procedures.

Usually the compounds of the invention were purified by medium pressureliquid chromatography, unless noted otherwise.

The following abbreviations are used in the examples:

-   Et₃N triethylamine-   CH₂Cl₂ dichloromethane-   CDCl₃ deuterated chloroform-   MeOH methanol-   CD₃OD deuterated methanol-   Na₂SO₄ sodium sulfate-   DMF N,N dimethylformamide-   EDCI 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide-   HOBt Hydroxybenzotriazole-   THF tetrahydrofuran-   ClCO₂Et ethylchloroformate-   NH₃ ammonia

The following synthetic schemes illustrate how compounds according tothe invention can be made. Those skilled in the art will be routinelyable to modify and/or adapt the following schemes to synthesize anycompound of the invention covered by Formula II.

Example 1 Intermediate 1 tert-Butyl(2S)-2-{[(4-Bromophenyl)carbamoyl]amino}-3-phenylpropanoate

To a solution of L-phenyl-alanine tert-butyl ester hydrochloride (100mg, 0.41 mmol) and 6 mL of methylene chloride at 25° C. was added4-bromo-phenyl isocyanate (81 mg, 0.41 mmol) and triethylamine (62 mg,0.62 mmol). The resulting mixture was stirred at 25° C. for 30 minutes.The mixture was concentrated and the residue was purified by mediumpressure liquid chromatography on silica gel using ethyl acetate:hexane(20:80) to yield Intermediate 1, as a white solid.

¹H NMR (CDCl₃, 300 MHz) δ: 7.20-7.35 (m, 5H), 7.13-7.20 (m, 2H),7.01-7.10 (m, 2H), 6.79 (br. s., NH), 5.52 (br. s., NH), 4.70 (t, J=6.2Hz, 1H), 2.91 (ddd, J=19.0 Hz, J=6.0 Hz, 2H), 1.47 (m, 9H).

Intermediates 2, 3 and 4 were prepared from the corresponding amino acidin a similar manner to the procedure described in Example 1 forIntermediate 1, starting with the appropriate amino acid. The resultsare described below in Table 1.

TABLE 1 Interm. IUPAC name No. Structure ¹H NMR δ (ppm) 2

¹H NMR (CDCl₃, 300 MHz) δ: 7.29-7.39 (m, 2H), 7.10-7.22 (m, 2H), 6.83(br. s., 1H), 4.44 (d, J = 4.4 Hz, 1H), 1.81-1.99 (m, 1H), 1.36-1.46 (m,1H), 1.08-1.31 (m, 1H) 0.86- 1.02 (m, 6H). 3

¹H NMR (CDCl₃, 300 MHz) δ: 7.26-7.36 (m, 2H), 7.09-7.18 (m, 2H), 6.95(br. s., NH), 4.40-4.50 (m, 1H), 1.73-189 (m, 1H), 1.52-1.72 (m, 1H),1.25-1.46 (m, 2H), 0.95 (t, 2H). 4

¹H NMR (CDCl₃, 300 MHz) δ: 7.20-7.33 (m, 2H), 7.04-7.15 (m, 2H), 4.44(dd, J = 9.1, 5.3 Hz, 1H), 1.74 (dd, J = 12.9, 6.4 Hz, 1H), 1.54-1.68(m, 1H), 1.50 (s, 9H), 1.40- 1.47 (m, 1H), 0.97 (d, J = 3.5 Hz, 3H),0.95 (d, 3H).

Example 2 Intermediate 5(2S)-2-{[(4-Bromophenyl)carbamoyl]amino}-3-phenylpropanoic Acid

A solution of Intermediate 1 (60 mg, 0.15 mmol) and 0.5 mL of formicacid was stirred at 25° C. for 3 hours. The resulting mixture wasquenched with water (1 mL) then extracted with ethyl acetate. Theorganic layer was washed with water, brine, dried over Na₂SO₄, filtered,and the filtrate was concentrated under reduced pressure. The residuewas rinsed 4 times with methylene chloride:hexane (1:1) to yieldIntermediate 5 as a white solid.

¹H NMR (acetone-d₆, 300 MHz) δ: 8.29 (s, NH), 7.40-7.50 (m, 2H),7.32-7.40 (m, 2H), 7.18-7.31 (m, 5H), 5.98 (d, J=7.9 Hz, NH), 4.67 (m,1H), 3.02 (ddd, J=19.0 Hz, J=6.0 Hz, 2H).

Intermediates 6, 7 and 8 and Compounds 1 through 6 were prepared fromthe corresponding urea derivative in a similar manner to the proceduredescribed in Example 2 for Intermediate 5. The results are describedbelow in Table 2.

TABLE 2 Interm. IUPAC name No. Structure ¹H NMR δ (ppm) 6(2S,3S)-2-{[(4-bromophenyl) ¹H NMR (acetone-d₆, 300 MHz) δ: 8.24carbamoyl]amino}-3- (br. s., 1H), 7.44-7.53 (m, 2H), 7.32-methylpentanoic acid 7.42 (m, 2H), 6.08 (d, J = 8.8 Hz, 1H),

4.44 (dd, J = 8.6, 4.8 Hz, 1H), 1.86-2.00 (m, J = 9.1, 6.9, 4.6, 4.6 Hz,1H), 1.43- 1.61 (m, 1H), 1.15-1.33 (m, 1H), 0.88- 1.04 (m, 6H). 7(2S)-2-{[(4-bromophenyl) ¹H NMR (acetone-d₆, 300 MHz) δ: 8.20carbamoyl]amino}-pentanoic (s, NH), 7.43-7.52 (m, 2H), 7.33-7.41 acid(m, 2H), 6.08 (d, J = 9.1 Hz, NH), 4.38-

4.50 (m, 1H), 1.77-1.92 (m, 1H), 1.61- 1.76 (m, 1H), 1.36-1.53 (m, 2H),0.89- 1.00 (m, 3H) 8 (2S)-2-{[(4-bromophenyl) ¹H NMR (acetone-d₆, 300MHz) δ: 8.17 (s, carbamoyl]amino}-4- NH), 7.43-7.51 (m, 2H), 7.35-7.41(m, methylpentanoic acid 2H), 6.04 (d, J = 9.1 Hz, NH), 4.42-4.53

(m, 1H), 1.73-1.88 (m, 1H), 1.53-1.73 (m, 2H), 0.97 (d, J = 2.1 Hz, 3H),0.95 (d, 3H). Comp. IUPAC name No. Structure ¹H NMR δ (ppm) 1{[(2S)-2-{[(4- ¹H NMR (acetone-d₆, 300 MHz) δ: 8.26 (s,bromophenyl)carbamoyl]amino}-3- NH), 7.71 (br. s., NH), 7.32-7.46 (m,phenylpropanoyl]amino}acetic 4H), 7.13-7.31 (m, 5H), 6.03 (d, J = acid8.5 Hz, NH), 4.71 (td, J = 7.7, 5.4 Hz, 1H),

3.98 (d, J = 5.9 Hz, 2H), 3.14-3.26 (m, 1H), 3.01 (dd, 1H). 23-{[(2S)-2-{[(4- ¹H NMR (acetone-d₆, 300 MHz) δ: 8.27 (s,bromophenyl)carbamoyl]amino}-3- NH), 7.44 (s, NH), 7.33-7.43 (m, 4H),phenylpropanoyl]amino}propanoic 7.15-7.30 (m, 5H), 6.03 (d, J = 7.9 Hz,acid NH), 4.53-4.65 (m, 1H), 3.34-3.51 (m,

2H), 2.93-3.15 (m, 2H), 2.47 (td, 2H). 3 {[(2S,3S)-2-{[(4-bromo-2- ¹HNMR (acetone-d₆, 300 MHz) δ: 8.28 (t, fluorophenyl)carbamoyl]amino-3- J= 8.9 Hz, 1H), 8.16 (br. s., NH), 7.67 (br. methylpentanoyl]amino}acetics., NH), 7.34 (dd, J = 11.0, 2.2 Hz, 1H), acid 7.23-7.30 (m, 1H), 6.57(d, J = 9.4 Hz,

NH), 4.37 (dd, J = 8.6, 5.7 Hz, 1H), 3.89- 4.08 (m, 2H), 1.86-1.98 (m,1H), 1.53- 1.67 (m, 1H), 1.10-1.27 (m, 1H), 0.98 (d, J = 6.7 Hz, 3H),0.85-0.94 (m, 3H). 4 {[(2S,3S)-2-{[(4- ¹H NMR (acetone-d₆, 300 MHz) δ:8.27 (s, bromophenyl)carbamoyl]amino}-3- NH), 7.66 (br. s., NH),7.42-7.51 (m, methylpentanoyl]amino}acetic 2H), 7.32-7.41 (m, 2H), 6.08(d, J = acid 8.2 Hz, NH), 4.34 (dd, J = 8.6, 5.7 Hz, 1H),

3.88-4.09 (m, 2H), 1.81-1.96 (m, 1H), 1.49-1.67 (m, 1H), 1.06-1.27 (m,1H), 0.97 (d, J = 6.7 Hz, 3H), 0.86-0.93 (m, 3H). 5 {[(2S)-2-{[(4- ¹HNMR (acetone-d₆, 300 MHz) δ: 8.25 (s, bromophenyl)carbamoyl]amino} NH),7.67 (br. s., NH), 7.41-7.51 (m, pentanoyl]amino}acetic 2H), 7.34-7.41(m, 2H), 6.13 (d, J = acid 7.9 Hz, NH), 4.42 (td, J = 7.7, 5.4 Hz, 1H),

3.89-4.08 (m, 2H), 1.73-1.89 (m, 1H), 1.54-1.69 (m, 1H), 1.34-1.51 (m,2H), 0.91 (t, J = 7.3 Hz, 3H). 6 {[(2S)-2-{[(4- ¹H NMR (acetone-d₆, 300MHz) δ: 8.19 (s, bromophenyl)carbamoyl]amino}-4- NH), 7.70 (br. s., NH),7.42-7.51 (m, methylpentanoyl]amino}acetic 2H), 7.33-7.41 (m, 2H), 6.07(d, J = acid 7.6 Hz, NH), 4.46 (ddd, J = 9.6, 8.3, 5.0 Hz,

1H), 3.87-4.07 (m, 2H), 1.72-1.86 (m, 1H), 1.61-1.72 (m, 1H), 1.46-1.59(m, 1H), 0.95 (s, 3H), 0.93 (s, 3H).

Example 3 Compound 7 tert-Butyl{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino}acetate

To a solution of Intermediate 5 (80 mg, 0.22 mmol) and 2 mL of anhydrousDMF at 25° C. was added EDCI (64 mg, 0.33 mmol), HOBt (45 mg, 0.33mmol), glycine tert-butyl ester (44 mg, 0.33 mmol) andN-methylmorpholine (44 mg, 0.44 mmol). The resulting mixture was stirredat 25° C. for 12 hours. The mixture was quenched with water (1 mL), andthe product was extracted with ethyl acetate (20 mL). The layers wereseparated, and the organic layer was washed with water, brine, driedover Na₂SO₄, filtered, and the filtrate was concentrated under reducedpressure. The resulting product was purified by medium pressure liquidchromatography on silica gel using ethyl acetate:hexane (40:60) to yieldCompound 7 as a white solid.

¹H NMR (CDCl₃, 300 MHz) δ: 7.18-7.35 (m, 7H), 7.03 (d, J=8.5 Hz, 2H),6.85 (br. s., 1H), 4.69 (t, J=7.5 Hz, 1H), 3.74-3.96 (m, 2H), 2.98-3.19(m, 2H), 1.42 (s, 9H).

Compounds 8 through 27 and Intermediate 9 were prepared from thecorresponding urea derivative in a similar manner to the proceduredescribed in Example 3 for Compound 7. The results are described belowin Table 3.

TABLE 3 Comp. IUPAC name No. Structure ¹H NMR δ (ppm)  8 tert-butyl3-{[(2S)-2-{[(4- ¹H NMR (CDCl₃, 300 MHz) δ: 7.18-bromophenyl)carbamoyl]amino}- 7.35 (m, 7H), 7.08-7.17 (m, 2H),3-phenylpropanoyl] 4.54-4.64 (m, 1H), 3.28-3.52 (m, amino}propanoate2H), 2.94-3.17 (m, 2H), 2.18-2.40

(m, 2H), 1.41 (s, 9H).  9 (2S)-2-{[(4-bromophenyl) ¹H NMR (CDCl₃, 300MHz) δ: 7.30- carbamoyl]amino}-N-(2- 7.37 (m, 2H), 7.17-7.30 (m, 7H),hydroxyethyl)-3-phenylpropanamide 4.50 (dd, J = 7.8, 6.3 Hz, 1H), 3.44-

3.59 (m, 2H), 3.23-3.30 (m, 2H), 3.05-3.15 (m, 1H), 2.90-3.01 (m, 1H).10 tert-butyl {[(2S,3S)-2-{[(4-bromo-2- ¹H NMR (CDCl₃, 300 MHz) δ: 7.92-fluorophenyl)carbamoyl]amino}-3- 7.99 (t, J = 8.9 Hz, 1H), 7.40 (br. s.,methylpentanoyl]amino}acetate NH), 7.07-7.16 (m, 2H), 6.67 (s,

NH), 6.54 (br. s., NH), 4.21-4.27 (m, 1H), 4.05-4.15 (m, 1H), 3.83- 3.92(m, 1H), 1.79-1.88 (m, 1H), 1.57-1.64 (m, 1H), 1.47 (s, 9H), 1.19-1.24(m, 1H), 1.00 (d, J = 6.7 Hz, 3H), 0.92 (t, 3H). 11 tert-butyl{[(2S,3S)-2-{[(4- ¹H NMR (CD₃OD, 300 MHz) δ: 8.55bromophenyl)carbamoyl]amino}-3- (s, NH), 8.36 (br. s., NH), 7.33-7.40methylpentanoyl]amino}acetate (m, 2H), 7.26-7.33 (m, 2H), 6.28

8.6, 6.3 Hz, 1H), 3.72-3.97 (m, 2H), 1.80-1.94 (m, 1H), 1.56-1.70 (m,1H), 1.45 (s, 9H), 1.13-1.31 (m, 1H), 1.01 (d, J = 6.7 Hz, 3H), 0.92-0.98 (m, 3H). 12 (2S,3S)-2-{[(4-bromophenyl) ¹H NMR (CD₃OD, 300 MHz) δ:7.34- carbamoyl]amino}-3-methyl-N-(2- 7.41 (m, 2H), 7.26-7.34 (m, 2H),oxopropyl)pentanamide 4.22 (d, J = 6.2 Hz, 1H), 4.05 (d, J =

8.2 Hz, 2H), 2.14 (s, 3H), 1.80-1.94 (m, 1H), 1.53-1.68 (m, 1H), 1.14-1.26 (m, 1H), 0.81-1.07 (m, 6H). 13 (2S,3S)-2-{[(4-bromo-2-fluorophenyl)¹H NMR (CD₃OD, 300 MHz) δ: 7.99 carbamoyl]amino}-3-methyl-N-(2- (t, J =8.8 Hz, 1H), 7.31 (dd, J = oxopropyl)pentanamide 10.7, 2.2 Hz, 1H),7.16-7.27 (m,

1H), 4.22 (d, J = 5.9 Hz, 1H), 3.94- 4.14 (m, 2H), 2.14 (s, 3H), 1.84-1.96 (m, 1H), 1.52-1.67 (m, 1H), 1.14-1.32 (m, 1H), 1.01 (d, J = 7.0 Hz,3H), 0.92-0.98 (m, 3H). 14 (2S,3S)-2-{[(4-bromophenyl) ¹H NMR (CD₃OD,300 MHz) δ: carbamoyl]amino}-N-(2- 7.33-7.42 (m, 2H), 7.26-7.33 (m,hydroxyethyl)-3-methylpentanamide 2H), 4.12 (d, J = 6.4 Hz, 1H), 3.55-

3.65 (m, 2H), 3.32-3.37 (m, 1H), 1.76-1.91 (m, 1H), 1.48-1.63 (m, 1H),1.09-1.31 (m, 2H), 0.90-0.99 (m, 6H). 15(2S,3S)-2-{[(4-bromo-2-fluorophenyl) ¹H NMR (CD₃OD, 300 MHz) δ:carbamoyl]amino}-N-(2- 7.99 (t, J = 8.6 Hz, 1H), 7.31 (dd, J =hydroxyethyl)-3-methylpentanamide 10.8, 2.3 Hz, 1H), 7.18-7.27 (m,

1H), 4.13 (d, J = 6.4 Hz, 1H), 3.56- 3.65 (m, 2H), 3.31-3.37 (m, 1H),1.77-1.89 (m, 1H), 1.50-1.61 (m, 1H), 1.10-1.26 (m, 1H), 0.88-1.01 (m,6H). 16 (2S)-2-{[(4-bromophenyl) ¹H NMR (acetone-d₆, 300 MHz) δ:carbamoyl]amino}-N-(2-oxopropyl)-3- 8.23 (s, NH), 7.59 (br. s., NH),7.32- phenylpropanamide 7.47 (m, 4H), 7.15-7.29 (m, 5H),

6.01 (d, J = 8.2 Hz, NH), 4.70 (td, J = 7.7, 5.7 Hz, 1H), 4.05 (d, J =5.3 Hz, 2H), 3.12-3.24 (m, 1H), 2.95- 3.06 (m, 1H), 2.10 (s, 3H). 17(2S)-2-{[(4-bromo-2-fluorophenyl) ¹H NMR (acetone-d₆, 300 MHz) δ:carbamoyl]amino}-N-(2-oxopropyl)-3- 8.22 (t, J = 8.9 Hz, 1H), 8.12 (br.s., phenylpropanamide NH), 7.61 (br. s., NH), 7.32 (dd, J =

11.0, 2.2 Hz, 1H), 7.15-7.29 (m, 6H), 6.51 (d, J = 7.3 Hz, NH), 4.72(td, J = 7.9, 5.6 Hz, 1H), 4.05 (dd, J = 5.6, 1.2 Hz, 2H), 3.14-3.24 (m,1H), 2.95-3.05 (m, 1H), 2.10 (s, 3H). 18 tert-butyl{[(2S)-2-{[(4-bromophenyl) ¹H NMR (acetone-d₆, 300 MHz) δ:carbamoyl]amino}-pentanoyl]amino} 8.20 (s, NH), 7.60 (br. s., NH), 7.42-acetate 7.51 (m, 2H), 7.32-7.41 (m, 2H),

6.07 (d, J = 7.6 Hz, NH), 4.41 (td, J = 7.9, 5.3 Hz, 1H), 3.75-3.99 (m,2H), 1.73-1.89 (m, 1H), 1.53-1.70 (m, 1H), 1.43 (s, 9H), 1.37-1.48 (m,2H), 0.92 (t, J = 7.3 Hz, 3H). 19 (2S)-2-{[(4-bromo-2-fluorophenyl) ¹HNMR (CD₃OD, 300 MHz) δ: carbamoyl]amino}-N-(2- 7.91 (t, J = 8.6 Hz, 1H),7.17-7.34 hydroxyethyl)-3-phenylpropanamide (m, 7H), 4.50 (dd, J = 8.2.6.2 Hz,

1H), 3.44-3.59 (m, 2H), 3.23-3.27 (m, 2H), 3.05-3.17 (m, 1H), 2.87- 2.99(m, 1H). 20 (2S)-2-{[(4-bromophenyl) ¹H NMR (CD₃OD, 300 MHz) δ: 7.33carbamoyl]amino}-N-(2- 7.33-7.41 (m, 2H), 7.25-7.33 (m, 2H),hydroxyethyl)pentanamid 4.23 (dd, J = 8.2, 5.6 Hz, 1H), 3.56-

3.63 (m, 2H), 1.69-1.84 (m, 1H), 1.54-1.68 (m, 1H), 1.29-1.51 (m, 2H),0.91-1.02 (m, 3H). 21 (2S)-2-{[(4-bromo-2-fluorophenyl) ¹H NMR (CD₃OD,300 MHz) δ: 7.97 carbamoyl]amino}-N-(2- (t, J = 8.6 Hz, 1H), 7.31 (dd, J= hydroxyethyl)pentanamide 10.7, 2.2 Hz, 1H), 7.19-7.27 (m,

1H), 4.23 (dd, J = 8.1, 5.4 Hz, 1H), 3.56-3.66 (m, 2H), 1.68-1.83 (m,1H), 1.54-1.68 (m, 1H), 1.34-1.51 (m, 2H), 0.91-1.03 (m, 3H). 22 methyl{[(2S)-2-{[(4-bromophenyl) ¹H NMR (acetone-d₆, 300 MHz) δ:carbamoyl]amino}- 8.19 (s, NH), 7.71 (br. s., NH), 7.42-pentanoyl]amino}acetate 7.52 (m, 2H), 7.31-7.42 (m, 2H),

6.07 (d, J = 8.2 Hz, NH), 4.34-4.47 (m, 1H), 3.86-4.10 (m, 2H), 3.66 (s,3H), 1.73-1.87 (m, 1H), 1.55-1.71 (m, 1H), 1.35-1.51 (m, 2H), 0.92 (t,3H). 23 ethyl {[(2S)-2-{[(4-bromophenyl) ¹H NMR (acetone-d₆, 300 MHz) δ:carbamoyl]amino}- 8.19 (s, NH), 7.69 (br. s., NH), 7.42-pentanoyl]amino}acetate 7.50 (m, 2H), 7.32-7.40 (m, 2H),

6.07 (d, J = 8.2 Hz, NH), 4.42 (td, J = 7.9, 5.6 Hz, 1H), 4.13 (q, J =7.2 Hz, 2H), 3.85-4.06 (m, 2H), 1.73- 1.88 (m, 1H), 1.55-1.69 (m, 1H),1.34-1.51 (m, 2H), 1.20 (t, J = 7.3, 3H), 0.92 (t. J = 7.3, 3H). 24isopropyl {[(2S)-2-{[(4-bromophenyl) ¹H NMR (acetone-d₆, 300 MHz) δ:carbamoyl]amino}-pentanoyl]amino} 8.20 (s, NH), 7.67 (br. s., NH), 7.43-acetate 7.51 (m, 2H), 7.33-7.42 (m, 2H),

6.07 (d, J = 9.7 Hz, NH), 4.97 (dt, J = 12.5, 6.2 Hz, 1H), 4.41 (td, J =7.8, 5.4 Hz, 1H), 3.82-4.04 (m, 2H), 1.73-1.89 (m, 1H), 1.55-1.70 (m,1H), 1.34-1.50 (m, 2H), 1.22 (s, 3H), 1.20 (s, 3H), 0.92 (t, J = 7.3,3H). 25 tert-butyl {[(2S)-2-{[(4-bromophenyl) ¹H NMR (acetone-d₆, 300MHz) δ: carbamoyl]amino}-4- 8.16 (s, NH), 7.62 (br. s., NH), 7.42-methylpentanoyl]amino}acetate 7.49 (m, 2H), 7.33-7.40 (m, 2H),

6.03 (d, J = 8.8 Hz, NH), 4.40-4.51 (m, 1H), 3.76-3.95 (m, 2H), 1.72-1.84 (m, 1H), 1.60-1.73 (m, 1H), 1.45-1.58 (m, 1H), 0.95 (s, 3H), 0.93(s, 3H). 26 (2S)-2-{[(4-bromophenyl) ¹H NMR (CD₃OD, 300 MHz) δ:carbamoyl]amino}-N-(2- 7.34-7.41 (m, 2H), 7.26-7.33 (m,hydroxyethyl)-4-methylpentanamide 2H), 4.24-4.33 (m, 1H), 3.55-3.64

(m, 2H), 3.32-3.35 (m, 2H), 1.64- 1.79 (m, 1H), 1.48-1.62 (m, 2H), 0.98(d, J = 4.1 Hz, 3H), 0.96 (d, J = 3.8 Hz, 3H). 27(2S)-2-{[(4-bromophenyl) ¹H NMR (acetone-d₆, 300 MHz) δ:carbamoyl]amino}-4-methyl-N-(2- 8.17 (s, NH), 7.61 (br. s., NH), 7.42-oxopropyl)pentanamide 7.50 (m, 2H), 7.32-7.42 (m, 2H),

6.06 (d, J = 8.5 Hz, NH), 4.45 (ddd, J = 9.7, 8.1, 5.0 Hz, 1H), 4.04 (d,J = 5.6 Hz, 2H), 2.12 (s, 3H), 1.72-1.84 (m, 1H), 1.60-1.72 (m, 1H),1.45- 1.58 (m, 1H), 0.95 (s, 3H), 0.93 (s, 3H). Interm. IUPAC name No.Structure ¹H NMR δ (ppm)  9 (2S)-2-{[(4-bromophenyl) ¹H NMR (acetone-d6,300 MHz) δ: carbamoyl]aminol-N- 10.27 (br. s., OH), 8.18 (br. s., NH),hydroxypentanamide 8.03 (s, NH), 7.42-7.50 (m, 2H),

7.32-7.41 (m, 2H), 6.11 (d, J = 9.1 Hz, NH), 4.23-4.34 (m, 1H), 1.52-1.80 (m, 2H), 1.27-1.49 (m, 2H), 0.87-0.95 (t, J = 7.3 Hz, 3H).

Example 4 Compound 28 (2S,3S)—N-(2-amino-2-oxoethyl)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanamide

To a solution of Compound 11 (50 mg, 0.13 mmol) and 5 mL of anhydroustetrahydrofuran under argon at −78° C. was added triethylamine (24 mg,0.17 mmol) and ethyl chloroformate (17 mg, 0.16 mmol). The mixture wasstirred at −78° C. for 30 minutes, and then ammonia gas was bubbled intoreaction flask for 1 minute. The resulting mixture was stirred at 25° C.for 2 hours. The reaction was quenched with water (1 mL), and theresidue was extracted with ethyl acetate (20 mL). The layers wereseparated, and the organic layer was washed with water, brine, driedover Na₂SO₄, filtered, and the filtrate was concentrated under reducedpressure. The resulting product was purified by medium pressurechromatography on silica gel using an eluent of methanol:dichloromethane(10:90) to yield to yield Compound 28 as a white solid.

¹H NMR (CD₃OD, 300 MHz) δ: 7.33-7.40 (m, 2H), 7.26-7.33 (m, 2H), 4.05(d, J=6.7 Hz, 1H), 3.85 (q, J=17.0 Hz, 2H), 1.78-1.91 (m, 1H), 1.54-1.69(m, 1H), 1.16-1.33 (m, 1H), 0.99 (d, J=6.7 Hz, 3H), 0.92-0.98 (m, 3H).

Compounds 29 through 85 as well as Intermediates 10 through 35 wereprepared from the corresponding acid derivative in a similar manner tothe procedure described in Example 4 for Compound 28.

TABLE 4 Comp. IUPAC name No. Structure ¹H NMR δ (ppm) 29(2S,3S)-N-(2-amino-2-oxoethyl)-2- ¹H NMR (CD₃OD, 300 MHz) δ: 8.00{[(4-bromo-2-fluorophenyl) (t, J = 8.6 Hz, 1H), 7.32 (dd, J = 10.7,carbamoyl]amino}-3- 2.2 Hz, 1H), 7.18-7.26 (m, 1H), 4.05methylpentanamide (d, J = 6.4 Hz, 1H), 3.74-3.95 (m, 2H),

1.80-1.91 (m, 1H), 1.51-1.69 (m, 1H), 1.18-1.32 (m, 1H), 1.00 (d, J =7.0 Hz, 3H), 0.92-0.98 (m, 3H). 30 (2S)-N-(2-amino-2-oxoethyl)-2- ¹H NMR(acetone-d₆, 300 MHz) δ: 8.27 {[(4-bromophenyl) (s, NH), 7.70 (br. s.,NH), 7.41-7.48 carbamoyl]amino}-pentanamide (m, 2H), 7.33-7.41 (m, 2H),7.02 (s,

NH), 6.30 (s, NH), 6.22 (d, J = 5.3 Hz, NH), 4.22-4.32 (m, 1H),3.72-3.91 (m, 2H), 1.73-1.88 (m, 1H), 1.56- 1.71 (m, 1H), 1.37-1.53 (m,2H), 0.88- 0.97 (m, 3H). 31 (2S)-N-(2-amino-2-oxoethyl)-2- ¹H NMR(acetone-d₆, 300 MHz) δ: 8.23 {[(4-bromo-2-fluorophenyl] (t, J = 8.8 Hz,1H), 8.13 (br. s., NH), carbamoyl}amino)pentanamide 7.72 (s, NH), 7.35(dd, J = 10.8, 2.3 Hz,

1H), 7.26 (dt, J = 8.9, 1.9 Hz, 1H), 7.00 (s, NH), 6.66 (d, J = 6.7 Hz,NH), 6.34 (s, NH), 4.29 (dd, J = 12.2, 8.1 Hz, 1H), 3.82 (dd, J = 5.9,1.8 Hz, 2H), 1.75- 1.90 (m, 1H), 1.58-1.73 (m, 1H), 1.37- 1.53 (m, 2H),0.89-0.98 (m, 3H). 32 (2S)-N-(2-amino-2-oxoethyl)-2- ¹H NMR (acetone-d₆,300 MHz) δ: 8.20 {[(4-bromophenyl) (s, NH), 7.77 (br. s., NH), 7.40-7.47carbamoyl]amino}-4- (m, 2H), 7.32-7.39 (m, 2H), 7.04 (br.methylpentanamide s., NH), 6.38 (br. s., NH), 6.18 (d, J =

7.3 Hz, NH), 4.31 (ddd, J = 9.4, 7.0, 5.3 Hz, 1H), 3.71-3.93 (m, 2H),1.69- 1.85 (m, 1H), 1.49-1.69 (m, 2H), 0.96 (d, J = 3.2 Hz, 3H), 0.93(d, J = 3.2 Hz, 3H). 33 tert-butyl {[(2S)-2-{[(4-bromo-2- ¹H NMR (CDCl₃,300 MHz) δ: 7.89 (t, fluorophenyl)carbamoyl]amino}- J = 8.8 Hz, 1H),7.55 (br. s., NH), 7.07 4-methylpentanoyl]amino}acetate (dd, J = 10.7,2.2 Hz, 1H), 6.95-7.04

(m, 1H), 6.84 (br. s., NH), 4.43 (br. s., NH), 4.00-4.16 (m, 1H),3.81-3.92 (m, 1H), 1.69-1.88 (m, 1H), 1.56- 1.70 (m, 2H), 1.47 (s, 9H),0.97 (d, J = 4.7 Hz, 3H), 0.95 (d, 3H). 34 {[(2S)-2-{[(4-bromo-2- ¹H NMR(acetone-d₆, 300 MHz) δ: 8.27 fluorophenyl)carbamoyl]amino}-4- (t, J =8.8 Hz, 1H), 8.07 (br. s., NH), methylpentanoyl]amino}acetic acid 7.71(br. s., NH), 7.34 (dd, J = 10.8,

2.1 Hz, 1H), 7.27 (dt, J = 8.8, 1.8 Hz, 1H), 6.54 (d, J = 8.8 Hz, NH),4.42-4.53 (m, 1H), 3.93-4.01 (m, 2H), 1.72- 1.86 (m, 1H), 1.63-1.74 (m,1H), 1.46- 1.60 (m, 1H), 0.96 (s, 3H), 0.93 (s, 3H). 35(2S)-2-{[(4-bromo-2-fluorophenyl) ¹H NMR (acetone-d₆, 300 MHz) δ: 8.30carbamoyl]amino}-4-methyl-N-(2- (t, J = 8.8 Hz, 1H), 8.06 (br. s., NH),oxopropyl)pentanamide 7.62 (br. s., NH), 7.31-7.38 (m, 2H),

7.24-7.30 (m, 2H), 6.52 (d, J = 8.2 Hz, NH), 4.39-4.53 (m, 1H), 4.04 (d,J = 5.6 Hz, 2H), 2.10-2.15 (m, 3H), 1.70- 1.86 (m, 1H), 1.61-1.71 (m,1H), 1.47- 1.62 (m, 1H), 0.96 (s, 3H), 0.93 (s, 3H). 36(2S)-2-{[(4-bromo-2-fluorophenyl) ¹H NMR (CD₃OD, 300 MHz) δ: 7.97 (t,carbamoyl]amino}-N-(2- J = 8.8 Hz, 1H), 7.31 (dd, J = 10.8,hydroxyethyl)-4- 2.3 Hz, 1H), 7.18-7.27 (m, 1H), 4.28 (dd,methylpentanamide J = 9.2, 5.4 Hz, 1H), 3.56-3.64 (m,

2H), 3.32-3.37 (m, 2H), 1.64-1.80 (m, 1H), 1.50-1.62 (m, 2H), 0.98 (d, J= 4.4 Hz, 3H), 0.96 (d, 3H). 37 (2S)-N-(2-amino-2-oxoethyl)-2-{[(4- ¹HNMR (acetone-d₆, 300 MHz) δ: 8.22 bromo-2-fluorophenyl) (t, J = 8.8 Hz,1H), 8.09 (br. s., NH), carbamoyl]amino}-4- 7.77 (br. s., NH), 7.34 (dd,J = 11.0, methylpentanamide 2.2 Hz, 1H), 7.25 (dt, J = 8.9, 1.7 Hz,

1H), 6.99 (br. s., NH), 6.62 (d, J = 7.0 Hz, NH), 6.37 (br. s., NH),4.33 (ddd, J = 9.6, 7.0, 5.1 Hz, 1H), 3.72-3.92 (m, 2H), 1.68-1.86 (m,1H), 1.49-1.70 (m, 2H), 0.96 (d, J = 3.5 Hz, 3H), 0.94 (d, 3H). 38tert-butyl (2S)-2-{[(2S)-2-{[(4- ¹H NMR (CDCl₃, 300 MHz) δ: 7.90 (t,bromo-2-fluorophenyl) J = 8.8 Hz, 1H), 7.45 (br. s., NH), 7.02-carbamoyl]amino}-4- 7.15 (m, 2H), 6.92 (s, NH), 6.61 (br.methylpentanoyl]amino}propanoate s., NH), 4.37-4.54 (m, 2H), 1.79 (dt,

J = 13.2, 6.9 Hz, 1H), 1.56-1.69 (m, 2H), 1.46 (s, 9H), 1.40 (d, J = 7.3Hz, 3H), 0.97 (s, 3H), 0.95 (s, 3H). 39 (2S)-2-{[(2S)-2-{[(4-bromo-2- ¹HNMR (acetone-d₆, 300 MHz) δ: 8.26 fluorophenyl)carbamoyl]amino}-4- (t, J= 8.9 Hz, 1H), 8.08 (br. s., NH), methylpentanoyl]amino}propanoic 7.67(d, J = 7.0 Hz, NH), 7.33 (dd, J = acid 10.8, 2.3 Hz, 1H), 7.27 (dt, J =8.8,

1.8 Hz, 1H), 6.52 (d, J = 9.1 Hz, NH), 4.40-4.54 (m, 2H), 1.72-1.87 (m,1H), 1.59-1.72 (m, 1H), 1.45-1.57 (m, 1H), 1.39 (d, J = 7.3 Hz, 3H),0.95 (s, 3H), 0.93 (s, 3H). 40 (2S)-N-[(1S)-2-amino-1-methyl-2- ¹H NMR(acetone-d₆, 300 MHz) δ: 8.25 oxoethyl]-2-{[(4-bromo-2- (t, J = 8.8 Hz,1H), 8.09 (br. s., NH), fluorophenyl)carbamoyl]amino}-4- 7.57 (d, J =5.6 Hz, NH), 7.35 (dd, J = methylpentanamide 11.0, 2.2 Hz, 1H),7.22-7.31 (m, 1H),

6.92 (br. s., NH), 6.54 (d, J = 7.3 Hz, NH), 6.29 (br. s., NH),4.30-4.44 (m, 2H), 1.73-1.90 (m, 1H), 1.47-1.72 (m, 2H), 1.30 (d, J =7.0 Hz, 3H), 0.95 (d, J = 1.5 Hz, 3H), 0.93 (d, 3H). 41 tert-butyl(2S)-2-{[(2S)-2-({[(4- ¹H NMR (CDCl₃, 300 MHz) δ: 7.62 (br.bromophenyl)carbamoyl}amino)-4- s., NH), 7.21-7.29 (m, 2H), 7.08-7.16methylpentanoyl]amino}propanoate (m, 2H), 6.90 (br. s., NH), 4.39-4.50

(m, 1H), 4.35 (t, J = 7.0 Hz, 1H), 1.73- 1.86 (m, 1H), 1.54-1.67 (m,2H), 1.45 (s, 9H), 1.38 (d, 3H), 0.97 (d, J = 2.9 Hz, 3H), 0.95 (d, J =2.9 Hz, 3H). 42 tert-butyl (2S)-2-{[(2S)-2-{[(4- ¹H NMR (CDCl₃, 300 MHz)δ: 7.45 (br. bromophenyl)carbamoyl]amino}- s., NH), 7.21-7.30 (m, 2H),7.10-7.18 4-methylpentanoyl]amino}-3- (m, 2H), 4.45 (t, J = 7.2 Hz, 1H),4.32 methylbutanoate (dd, J = 8.5, 5.0 Hz, 1H), 2.07-2.20

(m, 1H), 1.77 (dt, J = 13.3, 6.8 Hz, 1H), 1.56-1.67 (m, 2H), 1.47 (s,9H), 0.98 (d, J = 2.3 Hz, 3H), 0.96 (d, 3H), 0.93 (s, 3H), 0.91 (s, 3H).43 (2S)-2-{[(2S)-2-{[(4-bromophenyl) ¹H NMR (acetone-d₆, 300 MHz) δ:8.22 carbamoyl]amino}-4- (s, NH), 7.66 (d, J = 6.4 Hz, NH), 7.43-methylpentanoyl]amino}propanoic 7.50 (m, 2H), 7.34-7.41 (m, 2H), 6.05acid (d, J = 7.9 Hz, NH), 4.39-4.52 (m,

2H), 2.81 (br. s., 4H), 1.71-1.86 (m, 1H), 1.57-1.71 (m, 1H), 1.43-1.57(m, 1H), 1.39 (d, J = 7.3 Hz, 3H), 0.94 (s, 3H), 0.92 (s, 3H). 44(2S)-2-{[(2S)-2-{[(4-bromophenyl) ¹H NMR (acetone-d₆, 300 MHz) δ: 7.45carbamoyl]amino}-4- (br. s., NH), 7.21-7.30 (m, 2H), 7.10-methylpentanoyl]amino}-3- 7.18 (m, 2H), 4.45 (t, J = 7.2 Hz, 1H),methylbutanoic acid 4.32 (dd, J = 8.5, 5.0 Hz, 1H), 2.07-

2.20 (m, 1H), 1.77 (dt, J = 13.3, 6.8 Hz, 1H), 1.56-1.67 (m, 2H), 1.47(s, 9H), 0.98 (d, J = 2.3 Hz, 3H), 0.96 (d, 3H), 0.93 (s, 3H), 0.91 (s,3H). 45 (2S)-N-[(1S)-2-amino-1-methyl-2- ¹H NMR (acetone-d₆, 300 MHz) δ:8.21 oxoethyl]-2-{[(4-bromophenyl) (s, NH), 7.56 (s, NH), 7.42-7.49 (m,carbamoyl]amino}-4- 2H), 7.33-7.40 (m, 2H), 6.06-6.12 (s,methylpentanamide NH), 4.28-4.44 (m, 2H), 1.70-1.89

(m, 1H), 1.59-1.70 (m, 1H), 1.47- 1.59 (m, 1H), 1.30 (d, J = 7.3 Hz,3H), 0.95 (s, 3H), 0.92 (s, 3H). 46 (2S)-N-[(1S)-1-(amino-3methyl-1- ¹HNMR (CD₃OD, 300 MHz) δ: 7.34- oxobutan-2-yl]-2-{[(4- 7.40 (m, 2H),7.26-7.33 (m, 2H), 4.34 bromophenyl)carbamoyl]amino}- (dd, J = 9.5, 5.4Hz, 1H), 4.21 (d, J = 4-methylpentanamide 7.0 Hz, 1H), 2.02-2.16 (m,1H), 1.67-

1.79 (m, 1H), 1.51-1.65 (m, 1H), 0.94- 1.00 (m, 9H). 47(2S)-2-{[(4-bromophenyl) ¹H NMR (CD₃OD, 300 MHz) δ: 7.93carbamoyl]amino}-N-(2-hydroxy- (s, NH), 7.33-7.40 (m, 2H), 7.26-2-methylpropyl)-4- 7.33 (m, 2H), 6.28 (br. s., NH), 4.25-methylpentanamide 4.36 (m, 1H), 3.15-3.27 (m, 2H), 1.67-

1.81 (m, 1H), 1.50-1.67 (m, 2H), 1.17 (s, 6H), 0.99 (d, J = 4.7 Hz, 3H),0.97 (d, 3H). 48 (2S)-2-{[(4-bromophenyl) ¹H NMR (CD₃OD, 300 MHz) δ:7.33- carbamoyl]amino}-N-[2-hydroxy- 7.41 (m, 2H), 7.26-7.33 (m, 2H),4.30 1-(hydroxymethyl)ethyl]-4- (dd, J = 9.4, 5.6 Hz, 1H), 3.86-3.96methylpentanamide (m, 1H), 3.62 (t, J = 5.6 Hz, 4H), 1.67-

1.81 (m, 1H), 1.52-1.67 (m, 2H), 0.98 (d, J = 3.8 Hz, 3H), 0.96 (d, 3H).47 (2S)-2-{[(4-bromophenyl) ¹H NMR (CD₃OD, 300 MHz) δ: 7.33-carbamoyl]amino}-N-(2,3- 7.41 (m, 2H), 7.27-7.34 (m, 2H), 4.28dihydroxypropyl)-4- (dd, J = 8.9, 5.1 Hz, 1H), 3.64-3.76methylpentanamide (m, 1H), 3.46-3.52 (m, 2H), 3.33-

3.42 (m, 1H), 3.15-3.27 (m, 1H), 1.67- 1.80 (m, 1H), 1.48-1.67 (m, 2H),0.98 (d, J = 4.7 Hz, 3H), 0.96 (d, 3H). 48 (2S)-2-{[(4-bromophenyl) ¹HNMR (CD₃OD, 300 MHz) δ: 7.33- carbamoyl]amino}-N-[(1R)-2- 7.40 (m, 2H),7.26-7.32 (m, 2H), 4.26 hydroxy-1-methylethyl]-4- (dd, J = 8.2, 6.7 Hz,1H), 3.88-3.99 methylpentanamide (m, 1H), 3.49 (dd, J = 5.4, 1.3 Hz,2H),

1.72 (dt, J = 13.3, 6.8 Hz, 1H), 1.50- 1.60 (m, 2H), 1.14 (d, J = 6.7Hz, 3H), 0.98 (d, J = 3.8 Hz, 3H), 0.96 (d, 3H). 49 tert-butyl(2S)-2-{[(2S)-2-{[(4- ¹H NMR (CD₃OD, 300 MHz) δ: 7.33-bromophenyl)carbamoyl]amino}-4- 7.39 (m, 2H), 7.27-7.32 (m, 2H), 4.36methylpentanoyl]amino}propanoate (dd, J = 9.5, 5.4 Hz, 1H), 4.26 (dd, J=

8.6, 5.4 Hz, 1H), 1.49-1.84 (m, 6H), 1.45 (s, 9H), 1.36-1.43 (m, 1H),0.99 (d, J = 4.4 Hz, 3H), 0.97 (d, J = 4.1 Hz, 3H), 0.90-0.96 (m, 3H).50 tert-butyl (2S)-{[(2S)-2-{[(4- ¹H NMR (CD₃OD, 300 MHz) δ: 7.32-bromophenyl)carbamoyl]amino}-4- 7.43 (m, 6H), 7.25-7.31 (m, 2H), 4.41methylpentanoyl]amino}(phenyl)ethanoate (dd, J = 9.4, 5.3 Hz, 1H),1.72-1.81

(m, 1H), 1.49-1.70 (m, 2H), 1.40 (s, 9H), 1.17-1.19 (m, 0H), 0.99 (t, J= 6.7 Hz, 6H). 51 (2S)-2-{[(2S)-2-{[(4- ¹H NMR (CD₃OD, 300 MHz) δ: 7.33-bromophenyl)carbamoyl]amino}-4- 7.40 (m, 2H), 7.25-7.33 (m, 2H), 4.32-methylpentanoyl]amino}pentanoic 4.44 (m, 2H), 1.35-1.90 (m, 7H), acid0.99 (d, J = 3.8 Hz, 3H), 0.97 (d, J =

3.8 Hz, 3H), 0.91-0.96 (m, 3H). 52 (2S)-{[(2S)-2-{[(4- ¹H NMR (CD₃OD,300 MHz) δ: 7.40- bromophenyl)carbamoyl]amino}-4- 7.47 (m, 2H),7.23-7.39 (m, 7H), 4.41 methylpentanoyl]amino}(phenypethanoic (dd, J =9.4, 5.3 Hz, 1H), 1.70-1.84 acid (m, 1H), 1.48-1.69 (m, 2H), 0.98 (t,

6H). 53 (2S)-N-[(2S)-1-amino-1-oxopentan- ¹H NMR (CD₃OD, 300 MHz) δ:7.33- 2-yl]-2-{[(4- 7.41 (m, 2H), 7.26-7.33 (m, 2H), 4.30bromophenyl)carbamoyl]amino}-4- (ddd, J = 16.0, 9.4, 5.1 Hz, 1H), 1.50-methylpentanamide 1.86 (m, 5H), 1.33-1.48 (m, 2H), 0.95-

1.01 (m, 6H), 0.89-0.96 (m, 3H). 54 (2S)-N-[(1S)-2-amino-2-oxo-1- ¹H NMR(CD₃OD, 300 MHz) δ: 7.41- phenylethyl]-2-{[(4- 7.48 (m, 2H), 7.24-7.42(m, 7H), 4.36 bromophenyl)carbamoyl]amino}-4- (dd, J = 9.7, 5.0 Hz, 1H),1.52-1.82 methylpentanamide (m, 3H), 0.92-1.02 (m, 6H).

55 tert-butyl {[2-{[(4-bromophenyl) ¹H NMR (CDCl₃, 300 MHz) δ: 7.30-carbamoyl]amino}-2,4- 7.39 (m, 2H), 7.15-7.23 (m, 2H), 6.82dimethylpentanoyl]amino}acetate 1.79 (m, 2H), 1.63 (s, 3H), 1.48 (s,9H),

0.93 (d, J = 6.4 Hz, 3H), 0.89 (d, J = 6.2 Hz, 3H). 56{[2-{[(4-bromophenyl) ¹H NMR (CD₃OD, 300 MHz) δ: 7.31carbamoyl]amino}-2,4- (d, J = 14.4 Hz, 2H), 3.92 (d, J =dimethylpentanoyl]amino}acetic 1.2 Hz, 2H), 2.03-2.15 (m, 1H), 1.70-acid 1.86 (m, 2H), 1.58 (s, 3H), 0.95 (d, J =

6.4 Hz, 3H), 0.91 (d, J = 6.4 Hz, 3H). 57 tert-butyl{[2-{[(4-bromophenyl) ¹H NMR (CD₃OD, 300 MHz) δ: carbamoyl]amino}-2-7.247.39 (m, 2H), 7.24 (m, 2H), 6.50 (s, ethylbutanoyl]amino}acetateNH), 3.85 (s, 2H), 2.21-2.40 (m, 2H),

1.82 (dq, J = 14.2, 7.3 Hz, 2H), 1.45 (s, 9H), 0.85 (t, J = 7.3 Hz, 6H).58 {[2-{[(4-bromophenyl) ¹H NMR (CD₃OD, 600 MHz) δ: 7.35carbamoyl]amino}-2- (d, J = 8.8 Hz, 2H), 7.26-7.30 (m, 2H),ethylbutanoyl]amino}acetic acid 3.92 (s, 2H), 2.23-2.34 (m, 2H), 1.78-

1.89 (m, 2H), 0.85 (t, J = 7.5 Hz, 6H). 59 tert-butyl{[2-{[(4-bromophenyl) ¹H NMR (CDCl₃, 300 MHz) δ: 7.23carbamoyl]amino}-2- (m, 2H), 7.39 (m, 2H), 3.81 (s, 2H),methylpropanoyl]amino}acetate 1.52 (s, 6H), 1.45 (s, 9H).

60 {[2-{[(4-bromophenyl) ¹H NMR (CDCl₃, 300 MHz) δ: 7.23-carbamoyl]amino}-2- 7.40 (m, 4H), 3.81 (s, 2H), 1.51 (s, 6H).methylpropanoyl]amino}acetic acid

61 (2S)-2-{[(4-bromophenyl) ¹H NMR (CD₃OD, 300 MHz) δ: 7.34-carbamoyl]amino}-N-[2- 7.39 (m, 2H), 7.28-7.33 (m, 2H), 4.36(dimethylamino)-2-oxoethyl]-4- (dd, J = 10.0, 4.7 Hz, 1H), 3.97-4.13methylpentanamide (m, 2H), 3.03 (s, 3H), 2.94 (s, 3H), 1.51-

1.83 (m, 3H), 0.94-1.03 (m, 6H). 62 tert-butyl {[(2S)-4-methyl-2-({[4-¹H NMR (CD₃OD, 300 MHz) δ: 7.49- (trifluoromethyl)phenyl]carbamoyl} 7.56(m, 4H), 4.36 (dd, J = 9.7, 5.3 Hz, amino)pentanoyl]amino}acetate 1H),3.70-3.95 (m, 2H), 1.69-1.86

(m, 1H), 1.51-1.68 (m, 2H), 1.43- 1.46 (m, 9H), 0.99 (dd, J = 6.4, 4.1Hz, 6H). 63 {[(2S)-4-methyl-2-({[4- ¹H NMR (CD₃OD, 300 MHz) δ: 7.50-(trifluoromethyl)phenyl]carbamoyl} 7.56 (m, 4H), 6.37 (d, J = 7.6 Hz,NH), amino)pentanoyl]amino}acetic 4.38 (dd, J = 9.7, 5.0 Hz, 1H), 3.79-acid 4.04 (m, 2H), 1.69-1.87 (m, 1H), 1.50-

1.70 (m, 2H), 0.99 (dd, J = 6.4, 3.8 Hz, 6H). 64 tert-butyl{[(2R,3R)-2-{[(4- ¹H NMR (CD₃OD, 300 MHz) δ: 7.33-bromophenyl)carbamoyl]amino}-3- 7.39 (m, 2H), 7.26-7.32 (m, 2H), 6.29methylpentanoyl]amino}acetate (s, NH), 4.17-4.24 (m, 0H), 3.73-

3.95 (m, 2H), 1.87 (dtd, J = 9.8, 6.5, 3.2 Hz, 0H), 1.61 (ddt, J = 17.0,7.4, 3.6 Hz, 0H), 1.43-1.47 (m, 9H), 1.11- 1.27 (m, 0H), 0.90-1.03 (m,6H). 65 {[(2R,3R)-2-{[(4- ¹H NMR (CD₃OD, 300 MHz) δ: 7.33-bromophenyl)carbamoyl]amino}-3- 7.39 (m, 2H), 7.27-7.32 (m, 2H), 6.29methylpentanoyl]amino}acetic (s, NH), 4.19-4.26 (m, 1H), 3.81- acid 4.00(m, 2H), 1.84-1.94 (m, 1H), 1.60

(ddd, J = 13.2, 7.6, 3.5 Hz, 1H), 1.13- 1.30 (m, 2H), 1.13-1.30 (m, 2H),0.96 (d, J = 17.6 Hz, 3H). 66 tert-butyl {[(2R)-2-{[(4- ¹H NMR (CD₃OD,600 MHz) δ: 7.35- bromophenyl)carbamoyl]amino}-4- 7.38 (m, 2H),7.28-7.31 (m, 2H), 4.34 methylpentanoyl]amino}acetate (dd, J = 10.0, 5.0Hz, 1H), 3.75-3.91

(m, 2H), 1.73-1.80 (m, 1H), 1.63- 1.68 (m, 1H), 1.53-1.59 (m, 1H), 1.44-1.47 (m, 9H), 0.99 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H). 67{[(2R)-2-{[(4- ¹H NMR (CD₃OD, 600 MHz) δ: 7.34-bromophenyl)carbamoyl]amino}-4- 7.39 (m, 2H), 7.26-7.32 (m, 2H), 4.32-methylpentanoyl]amino}acetic 4.38 (m, 1H), 3.84-4.00 (m, 2H), acid1.72-1.81 (m, 1H), 1.63-1.70 (m,

1H), 1.52-1.60 (m, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.7 Hz,3H). 68 tert-butyl {[(2S)-4-methyl-2-({[4- ¹H NMR (CD₃OD, 300 MHz) δ:7.27- (methylsulfanyl)phenyl]carbamoyl} 7.34 (m, 2H), 7.17-7.24 (m, 2H),6.24 amino)pentanoyl]amino}acetate (d, J = 7.9 Hz, NH), 4.30-4.40 (m,

1H), 3.72-3.95 (m, 2H), 2.40-2.43 (m, 3H), 1.69-1.84 (m, 1H), 1.50- 1.68(m, 2H), 1.44-1.47 (m, 9H), 0.99 (dd, J = 6.4, 4.7 Hz, 6H). 692-methyl-2-{[(2S)-4-methyl-2-({[4- ¹H NMR (CD₃OD, 300 MHz) δ: 8.27(trifluoromethyl)phenyl]carbamoyl} (s, NH), 7.52 (d, J = 19.9 Hz, 4H),6.29 amino)pentanoyl]amino}propanoic acid (d, J = 8.5 Hz, NH), 4.27-4.43(m,

1H), 1.70-1.85 (m, 1H), 1.45-1.67 (m, 8H), 0.98 (dd, J = 6.4, 2.9 Hz,6H). 70 {[(2S)-4-methyl-2-({[4- ¹H NMR (CD₃OD, 300 MHz) δ: 7.26-(methylsulfanyl)phenyl]carbamoyl} 7.34 (m, 2H), 7.17-7.24 (m, 2H), 4.30-amino)pentanoyl]amino}acetic 4.41 (m, 1H), 3.80-4.03 (m, 2H), acid2.39-2.43 (m, 3H), 1.49-1.84 (m,

3H), 0.98 (dd, J = 6.4, 4.1 Hz, 6H). 71 tert-butyl({(2S)-4-methyl-2-[({4- ¹H NMR (CD₃OD, 300 MHz) δ: 7.52-[(trifluoromethyl)sulfanyl]phenyl} 7.57 (m, 2H), 7.47-7.52 (m, 2H),4.32- carbamoyl)amino]pentanoyl}amino) 4.40 (m, 1H), 3.72-3.95 (m, 2H),acetate 1.69-1.84 (m, 1H), 1.50-1.68 (m,

2H), 1.42-1.47 (m, 9H), 0.99 (dd, J = 6.3, 4.2 Hz, 6H). 72({(2S)-4-methyl-2-[({4- ¹H NMR (CD₃OD, 300 MHz) δ: 7.47-[(trifluoromethyl)sulfanyl]phenyl} 7.57 (m, 4H), 4.37 (dd, J = 9.5, 5.1Hz, carbamoyl)amino]pentanoyl}amino) 1H), 3.83-4.02 (m, 2H), 1.70-1.83acetic acid (m, 1H), 1.51-1.68 (m, 2H), 0.99 (d, J =

3.8 Hz, 3H), 0.97 (d, J = 3.8 Hz, 3H). 73 tert-butyl 2-{[(2S)-2-{[(4- ¹HNMR (CD₃OD, 300 MHz) δ: 7.33- bromophenyl)carbamoyl]amino}-4- 7.38 (m,2H), 7.26-7.32 (m, 2H), 4.31 methylpentanoyl]amino}-2- (dd, J = 9.1, 5.6Hz, 1H), 1.67-1.80 methylpropanoate (m, 1H), 1.45-1.63 (m, 2H), 1.39-

1.44 (m, 15H), 0.97 (dd, J = 6.6, 3.1 Hz, 6H). 74 2-{[(2S)-2-{[(4- ¹HNMR (CD₃OD, 300 MHz) δ: 8.46 bromophenyl)carbamoyl]amino}-4- (s, NH),8.26 (s, NH), 7.33-7.38 (m, methylpentanoyl]amino}-2- 2H), 7.25-7.31 (m,2H), 4.32 (dd, J = methylpropanoic acid 9.2, 5.4 Hz, 1H), 1.68-1.80 (m,1H),

1.51-1.65 (m, 2H), 1.49 (s, 3H), 1.48 (s, 3H), 0.98 (d, J = 3.5 Hz, 3H),0.96 (d, J = 3.5 Hz, 3H). 75 tert-butyl {[(2S)-4-methyl-2-({[4- ¹H NMR(CD₃OD, 300 MHz) δ: 7.61 (methylsulfinyl)phenyl]carbamoyl} (s, 4H), 4.37(dd, J = 9.8, 5.1 Hz, 1H), amino)pentanoyl]amino}acetate 3.72-3.96 (m,2H), 2.77 (s, 3H), 1.69-

1.85 (m, 1H), 1.51-1.69 (m, 2H), 1.45 (s, 9H), 0.94-1.05 (m, 6H). 76tert-butyl {[(2S)-4-methyl-2-({[4- ¹H NMR (CD₃OD, 300 MHz) δ: 7.77-(methylsulfonyl)phenyl]carbamoyl} 7.86 (m, 2H), 7.57-7.67 (m, 2H), 4.37amino)pentanoyl]amino}acetate (dd, J = 9.7, 5.0 Hz, 1H), 3.71-3.96

(m, 2H), 3.07 (s, 3H), 1.69-1.83 (m, 1H), 1.51-1.70 (m, 2H), 1.40-1.49(m, 9H), 0.94-1.03 (m, 6H). 77 {[(2S)-4-methyl-2-({[4- ¹H NMR (CD₃OD,300 MHz) δ: 7.57- (methylsulfinyl)phenyl]carbamoyl} 7.66 (m, 4H), 4.38(dd, J = 9.7, 5.0 Hz, amino)pentanoyl]amino}acetic 1H), 3.81-4.03 (m,2H), 2.77 (s, 3H), acid 1.69-1.85 (m, 1H), 1.48-1.68 (m,

2H), 0.92-1.03 (m, 6H). 78 {[(2S)-4-methyl-2-({[4- ¹H NMR (CD₃OD, 300MHz) δ: 7.76- (methylsulfonyl)phenyl]carbamoyl} 7.87 (m, 2H), 7.57-7.68(m, 2H), 6.43 amino)pentanoyl]amino}acetic (d, J = 8.5 Hz, NH),4.32-4.45 (m, acid 1H), 3.81-4.04 (m, 2H), 3.07 (s, 3H),

1.71-1.83 (m, 1H), 1.49-1.70 (m, 2H), 0.98 (dd, J = 6.4, 3.5 Hz, 6H). 79tert-butyl 2-methyl-2-{[(2S)-4- ¹H NMR (CD₃OD, 300 MHz) δ: 7.46-methyl-2-({[4- 7.58 (m, 2H), 4.33 (dd, J = 9.2, 5.7 Hz,(trifluoromethyl)phenyl]carbamoyl} 1H), 1.69-1.86 (m, 1H), 1.46-1.66amino)pentanoyl]amino}propanoate (m, 2H), 1.36-1.46 (m, 15H), 0.94-

1.04 (m, 6H). 80 tert-butyl {[(2S)-2-{[(4- ¹H NMR (CD₃OD, 300 MHz) δ:7.24- bromophenyl)carbamoyl]amino}-4- 7.41 (m, 4H), 4.44 (dd, J = 7.8,5.4 Hz, (methylsulfanyl)butanoyl]amino}acetate 1H), 3.70-3.99 (m, 2H),2.54-2.68

(m, 2H), 2.12-2.18 (m, 1H), 2.11 (s, 3H), 1.85-2.02 (m, 1H), 1.41-1.50(m, 9H). [α]D = −21.8 (c = 1.00, MeOH) 81 tert-butyl {[(2S)-2-{[(4- ¹HNMR (CD₃OD, 300 MHz) δ: 7.26- bromophenyl)carbamoyl]amino}-4- 7.43 (m,4H), 4.43-4.57 (m, 1H), 3.70- (methylsulfonyl)butanoyl]amino}acetate4.03 (m, 2H), 3.24 (s, 2H), 2.99 (s,

4H), 2.28-2.42 (m, 1H), 2.11-2.26 (m, 1H), 1.47 (s, 9H). 82{[(2S)-2-{[(4- ¹H NMR (CD₃OD, 300 MHz) δ: 7.25-bromophenyl)carbamoyl]amino}-4- 7.44 (m, 4H), 6.55 (d, J = 7.3 Hz, NH),(methylsulfanyl)butanoyl]amino}acetic 4.53 (m, 1H), 3.79-4.10 (m, 2H),3.26 acid (m, 2H), 2.98 (s, 3H), 2.26-2.42 (m,

1H), 2.20 (m, 1H). 83 {[(2S)-2-{[(4- ¹H NMR (CD₃OD, 300 MHz) δ: 7.26-bromophenyl)carbamoyl]amino}-4- 7.42 (m, 4H), 6.55 (d, J = 7.3 Hz, NH),(methylsulfonyl)butanoyl]amino}acetic 4.47-4.58 (m, 1H), 3.80-4.11 (m,acid 2H), 3.25 (m, 2H), 2.98 (s, 3H), 2.28-

2.43 (m, 1H), 2.11-2.27 (m, 1H). 84 tert-butyl {[2-{[(4- ¹H NMR (CD₃OD,300 MHz) δ: 7.61 bromophenyl)carbamoyl]amino}-3- (s, 1H), 7.21-7.41 (m,4H), 6.94 (s, (1H-imidazol-4- 1H), 4.51-4.64 (m, 1H), 3.75-3.96yl)propanoyl]amino}acetate (m, 2H), 3.07-3.22 (m, 1H), 2.93-

3.06 (m, 1H), 1.49 (s, 9H). 85 {[2-{[(4- ¹H NMR (DMSO-D₆, 300MHz) δ:8.93 bromophenyl)carbamoyl]amino}-3- (NH, 1H), 8.42 (br. s., NH), 7.67(s, (1H-imidazol-4- 1H), 7.34 (d, J = 4.1 Hz, 4H), 6.88 (s,yl)propanoyl]amino}acetic 1H), 6.28 (d, J = 7.3 Hz, NH), 4.44 (m, acid1H), 3.55-3.90 (m, 2H), 2.93 (m., 2H).

86 tert-butyl 2-{[(2R)-2-{[(4- ¹H NMR (CD₃OD, 300 MHz) δ: 7.33-bromophenyl)carbamoyl]amino}-4- 7.38 (m, 2H), 7.26-7.32 (m, 2H), 4.31methylpentanoyl]amino}-2- (dd, J = 9.1, 5.6 Hz, 1H), 1.67-1.80methylpropanoate (m, 1H), 1.45-1.63 (m, 2H), 1.39-

1.44 (m, 15H), 0.97 (dd, J = 6.6, 3.1 Hz, 6H). 872-{[(2R)-2-{[(4-bromophenyl) ¹H NMR (CD₃OD, 300 MHz) δ: 8.46carbamoyl]amino}-4- (s, NH), 8.23 (s, 2NH), 7.33-7.39 (m,methylpentanoyl]amino}-2- 2H), 7.26-7.31 (m, 2H), 6.19 (d, J =methylpropanoic acid 8.2 Hz, NH), 4.31 (m 1H), 1.73 (m,

1H), 1.51-1.65 (m, 2H), 1.49 (s, 3H), 1.48 (s, 3H), 0.98 (d, J = 3.8 Hz,6H), 0.96 (d, J = 3.5 Hz, 6H). 88 tert-butyl {[4-amino-2-{[(4- ¹H NMR(CD₃OD, 300 MHz) δ: 7.27- bromophenyl)carbamoyl]amino}- 7.42 (m, 4H),4.69 (t, J = 6.0 Hz, 1H), 4-oxobutanoyl]amino}acetate 3.75-3.94 (m, 2H),2.70-2.78 (m,

2H), 1.45 (s, 9H). 89 4-amino-2-{[(4-bromophenyl) ¹H NMR (CD₃OD, 300MHz) δ: 7.26- carbamoyl]amino}-4-oxobutanoic 7.44 (m, 4H), 4.62 (t, J =5.3 Hz, 1H) acid 2.70-2.94 (m, 2H).

90 tert-butyl {[2-{[(4-bromophenyl) ¹H NMR (CD₃OD, 300 MHz) δ: 7.56-carbamoyl]amino}-3-(1H-indol-3- 7.61 (m, 1H), 7.30-7.36 (m, 3H), 7.23-yl)propanoyl]amino}acetate 7.26 (m, 2H), 7.16 (s, NH), 7.08 (td,

J = 7.6, 1.2 Hz, 1H), 6.95-7.02 (m, 1H), 6.13 (d, J = 7.3 Hz, NH),4.60-4.68 (m, 1H), 3.80 (s, 2H), 3.32-3.38 (m, 1H), 3.11-3.23 (m, 1H),1.43-1.47 (m, 9H). 91 tert-butyl {[4-amino-2-{[(4- ¹H NMR (CD₃OD, 300MHz) δ: 7.27- bromophenyl)carbamoyl]amino}- 7.42 (m, 4H), 4.69 (t, J =6.0 Hz, 1H), 4-oxobutanoyl]amino}acetate 3.75-3.94 (m, 2H), 2.70-2.78(m,

2H), 1.45 (s, 9H). Interm. IUPAC name No. Structure ¹H NMR δ (ppm) 10(2S,3S)-2-{[(4-bromophenyl) ¹H NMR (CD₃OD, 300 MHz) δ: 7.33-carbamoyl]amino}-3- 7.41 (m, 2H), 7.26-7.33 (m, 2H), 4.18methylpentanamide (d, J = 6.2 Hz, 1H), 1.74-1.91 (m, 1H),

1.50-1.66 (m, 1H), 1.11-1.33 (m, 1H), 0.99 (d, J = 7.0 Hz, 3H), 0.91-0.97 (m, 3H). 11 (2S,3S)-2-{[(4-bromo-2- ¹H NMR (CD₃OD, 300 MHz) δ: 7.99fluorophenyl)carbamoyl]amino}-3- (t, J = 8.8 Hz, 1H), 7.31 (dd, J =10.7, methylpentanamide 2.2 Hz, 1H), 7.19-7.27 (m, 1H), 4.18

(d, J = 6.2 Hz, 1H), 1.78-1.95 (m, 1H), 1.49-1.65 (m, 1H), 1.10-1.27 (m,1H), 1.00 (d, J = 6.7 Hz, 3H), 0.91- 0.98 (m, 3H). 12(2S)-2-{[(4-bromo-2-fluorophenyl) ¹H NMR (acetone-d6, 300 MHz) δ:carbamoyl]amino}-pentanamide 8.28 (t, J = 8.8 Hz, 1H), 8.12 (br. s.,

NH), 7.33 (dd, J = 11.0, 2.2 Hz, 1H), 7.26 (dt, J = 8.9, 1.9 Hz, 1H),7.07 (br. s., NH), 6.55 (d, J = 7.0 Hz, NH), 6.40 (br. s., NH), 4.38(td, J = 7.8, 5.3 Hz, 1H), 1.73-1.89 (m, 1H), 1.54-1.70 (m, 1H),1.24-1.49 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13 (2S)-2-{[(4-bromophenyl)¹H NMR (acetone-d6, 300 MHz) δ: carbamoyl]amino}-4- 8.17 (s, NH),7.41-7.50 (m, 2H), 7.33- methylpentanamide 7.40 (m, 2H), 6.03 (d, J =8.2 Hz,

NH), 4.39 (ddd, J = 9.4, 8.2, 5.0 Hz, 1H), 3.58 (q, J = 5.6 Hz, 2H),3.26- 3.37 (m, 2H), 1.66-1.81 (m, 1H), 1.44- 1.67 (m, 2H), 0.94 (d, J =1.5 Hz, 3H), 0.92 (d, J = 1.4 Hz, 3H). 14(2S)-2({[(4-bromo-2-fluorophenyl) ¹H NMR (acetone-d6, 300 MHz) δ: 8.27carbamoyl]amino}-4- (t, J = 8.9 Hz, 1H), 8.06 (br. s., NH),methylpentanoate 7.34 (dd, J = 10.8, 2.3 Hz, 1H), 7.25-

7.31 (m, 1H), 6.53 (d, J = 7.0 Hz, NH), 4.43-4.55 (m, 1H), 1.73-1.87 (m,1H), 1.53-1.71 (m, 2H), 0.98 (d, J = 1.5 Hz, 3H), 0.96 (d, J = 1.5 Hz,3H). 15 (2S)-2-{[(4-bromo-2-fluorophenyl) ¹H NMR (acetone-d6, 300 MHz)δ: 8.28 carbamoyl]amino}-4- (t, J = 8.9 Hz, 1H), 8.07 (br. s., NH),methylpentanamide 7.33 (dd, J = 10.8, 2.3 Hz, 1H), 7.23-

7.30 (m, 1H), 7.10 (br. s., NH), 6.50 (d, J = 8.2 Hz, NH), 6.38 (br. s.,NH), 4.42 (ddd, J = 9.6, 8.3, 5.0 Hz, 1H), 1.70- 1.87 (m, 1H), 1.59-1.70(m, 1H), 1.44- 1.59 (m, 1H), 0.95 (d, J = 1.5 Hz, 3H), 0.93 (d, 3H). 16tert-butyl (2S)-2-{[(4-bromo-2- ¹H NMR (CDCl₃, 300 MHz) δ: 7.89 (t,fluorophenyl)carbamoyl]amino}-4- J = 8.8 Hz, 1H), 7.14 (dd, J = 10.4,2.2 Hz, methylpentanoate 1H), 7.06 (d, J = 9.1 Hz, 1H), 6.80

(d, J = 2.6 Hz, NH), 5.79 (br. s., NH), 4.45 (dd, J = 8.8, 5.0 Hz, 1H),1.69- 1.85 (m, 1H), 1.57-1.69 (m, 1H), 1.52 (s, 9H), 1.41-1.48 (m, 1H),0.97 (d, J = 3.5 Hz, 3H), 0.95 (d, 3H). 17 2-{[(4-bromophenyl) ¹H NMR(CD₃OD, 300 MHz) δ: 7.31- carbamoyl]amino}-2,4- 7.39 (m, 2H), 7.22-7.30(m, 2H), 1.80- dimethylpentanoic acid 1.92 (m, 2H), 1.71-1.82 (m, 1H),

1.56-1.67 (m, 2H), 1.44 (s, 3H), 0.98 (d, J = 1.2 Hz, 3H), 0.95 (d, J =1.2 Hz, 3H). 18 tert-butyl {[2-{[(4-bromophenyl) ¹H NMR (CD₃OD, 300 MHz)δ: 9.29 carbamoyl]amino}-2- (br. s., NH), 8.58-8.75 (m, 4H), 7.33methylpropanoate (br. s., NH), 2.65-2.75 (m, 9H).

19 2-{[(4-bromophenyl) ¹H NMR (CD3OD, 300 MHz) δ: 7.32-carbamoyl]amino}-2- 7.37 (m, 2H), 7.24-7.29 (m, 2H), 1.52methylpropanoic acid (s, 6H).

20 2- {[(4-bromophenyl) ¹H NMR (acetone-d6, 300 MHz) δ:carbamoyl]amino}-2-ethylbutanoic 8.76 (br. s., 1H), 7.44-7.52 (m, 2H),acid 7.31-7.40 (m, 2H), 6.30 (br. s., 1H),

2.29-2.48 (m, 2H), 1.75-1.92 (m, 2H), 0.76-0.86 (m, 6H). 21 tert-butyl(2S)-4-methyl-2-({[4- ¹H NMR (CD₃OD, 300 MHz) δ: 7.50(trifluoromethyl)phenyl]carbamoyl} (s, 4H), 4.27 (dd, J = 9.1, 5.6 Hz,1H), amino)pentanoate 1.68-1.86 (m, 1H), 1.52-1.66 (m,

2H), 1.45-1.50 (s, 9H), 0.95 (t, J = 6.9 Hz, 6H). 22(2S)-4-methyl-2-({[4- ¹H NMR (CD₃OD, 300 MHz) δ: 7.49-(trifluoromethyl)phenyl]carbamoyl} 7.57 (m, 4H), 4.38 (dd, J = 9.4, 5.0Hz, amino)pentanoic acid 1H), 1.69-1.87 (m, 1H), 1.51-1.69

(m, 2H), 0.92-1.01 (m, 6H). 23 tert-butyl (2S)-2-({(4-chlorophenyl) ¹HNMR (CD₃OD, 300 MHz) δ: 7.30- carbamoyl}amino)4- 7.39 (m, 2H), 7.17-7.28(m, 1H), 4.25 methylpentanoate (dd, J = 8.9, 5.7 Hz, 1H), 1.74 (dd, J =

13.6, 7.5 Hz, 1H), 1.51-1.67 (m, 2H), 1.47 (s, 9H), 0.97 (t, J = 6.9 Hz,6H). 24 (2S)-2-({(4-chlorophenyl) ¹H NMR (CD₃OD, 300 MHz) δ: 7.29-carbamoyl}amino)4- 7.38 (m, 2H), 7.17-7.27 (m, 2H), 4.36 methylpentanoicacid (dd, J = 9.4, 5.0 Hz, 1H), 1.73 (dd, J =

18.3, 5.7 Hz, 1H), 1.51-1.68 (m, 2H), 0.98 (dd, J = 6.4, 3.5 Hz, 6H). 25tert-butyl (2S)-2-({(4-iodophenyl) ¹H NMR (CD₃OD, 300 MHz) δ: 7.50-carbamoyl}amino)4- 7.59 (m, 2H), 7.12-7.23 (m, 2H), 4.25methylpentanoate (m, 1H), 1.73 (m, 1H), 1.49-1.63 (m,

2H), 1.47 (s, 9H), 0.91-1.03 (m, 6H). 26 (2S)-2-({(4-iodophenyl) ¹H NMR(CD₃OD, 300 MHz) δ: 7.50- carbamoyl}amino)4- 7.58 (m, 2H), 7.13-7.21 (m,2H), 4.35 methylpentanoic acid (dd, J = 9.4, 5.0 Hz, 1H), 1.50-1.86

(m, 2H), 1.01 (m, 6H). 27 (2R,3R)-2-({(4-bromophenyl) ¹H NMR (CD₃OD, 300MHz) δ: 7.35- carbamoyl}amino)3- 7.39 (m, 2H), 7.28-7.32 (m, 2H), 4.32methylpentanoic acid (d, J = 4.7 Hz, 1H), 1.92 (dq, J = 6.8,

4.6 Hz, 1H), 1.46-1.60 (m, 1H), 1.16- 1.33 (m, 1H), 0.93-1.02 (m, 6H).28 tert-butyl (2R)-2-({(4- ¹H NMR (CDCl₃, 300 MHz) δ: 7.33 (d,bromophenyl)carbamoyl}amino)4- J = 8.5 Hz, 2H), 7.17 (s, 2H), 4.43 (dd,methylpentanoate J = 9.1, 5.3 Hz, 1H), 1.68-1.79 (m,

1H), 1.56-1.67 (m, 1H), 1.48 (s, 9H), 1.44 (s, 1H), 0.97 (d, J = 4.1 Hz,3H), 0.95 (d, J = 4.4 Hz, 3H). 29 (2R)-2-({(4-bromophenyl) ¹H NMR(acetone-D6, 300 MHz) δ: carbamoyl}amino)4- 8.17 (s, NH), 7.43-7.50 (m,2H), 7.33- methylpentanoic acid 7.41 (m, 2H), 6.04 (d, J = 7.9 Hz,

NH), 4.42-4.52 (m, 1H), 1.71-1.87 (m, 1H), 1.52-1.69 (m, 2H), 0.97 (d, J= 2.1 Hz, 3H), 0.95 (d, J = 2.3 Hz, 3H). 30 tert-butyl(2S)-4-methyl-2-({[4- ¹H NMR (CD3OD, 300 MHz) δ: 7.27-(methylthio)phenyl] 7.32 (m, 2H), 7.18-7.23 (m, 2H), 4.22-carbamoyl}amino)pentanoate 4.29 (m, 1H), 2.42 (s, 3H), 1.70-1.79

(m, 1H), 1.51-1.61 (m, 2H), 1.47 (s, 9H), 0.97 (t, J = 6.7 Hz, 6H). 31(2S)-4-methyl-2-({[4- ¹H NMR (CD3OD, 300 MHz) δ: 7.25-(methylthio)phenyl] 7.31 (m, 2H), 7.14-7.20 (m, 2H), 4.37carbamoyl}amino)pentanoic acid (dd, J = 9.2, 5.1 Hz, 1H), 2.39 (s, 3H),

1.68-1.83 (m, 1H), 1.51-1.67 (m, 2H), 0.96 (dd, J = 6.2, 2.3 Hz, 6H). 32(2S)-4-methyl-2-{({4- ¹H NMR (CD3OD, 300 MHz) δ: 7.52-[(trifluoromethyl)thio]phenyl} 7.58 (m, 2H), 7.47-7.52 (m, 2H), 4.37carbamoyl}amino)pentanoic acid (dd, J = 9.4, 5.0 Hz, 1H), 1.70-1.82

(m, 1H), 1.53-1.69 (m, 2H), 0.99 (d, J = 3.2 Hz, 3H), 0.97 (d, J = 3.2Hz, 3H). 33 tert-butyl (2S)-4-methyl-2-{({4- ¹H NMR (CD3OD, 300 MHz) δ:7.53- [(trifluoromethyl)thio]phenyl} 7.57 (m, 2H), 7.47-7.51 (m, 2H),4.26 carbamoyl}amino)pentanoate (dd, J = 8.9, 5.7 Hz, 1H), 1.74 (td, J =

13.6, 6.7 Hz, 1H), 1.51-1.65 (m, 2H), 1.47 (s, 9H), 0.97 (t, J = 6.7 Hz,6H). 34 (2S)-2-({(4-bromophenyl) ¹H NMR (CD₃OD, 300 MHz) δ: 7 23-carbamoyl}amino)4- 7.41 (m, 4H), 4.31-4.42 (m, 1H), 2.56(methylthio)butanoic acid (d, J = 15.5 Hz, 2H), 2.12-2.23 (m,

1H), 2.08 (s, 3H), 1.98 (dt, J = 14.0, 7.2 Hz, 1H). 352-({(4-bromophenyl) ¹H NMR (CD₃OD, 300 MHz) δ: 8.76carbamoyl}amino)3-(1H-imidazol- (s, 1H), 7.23-7.40 (m, 6H), 4.65 (m,4-yl)propanoic acid 1H), 3.03-3.27 (m, 2H).

BIOLOGICAL DATA

Biological activity of compounds according to Formula II is set forth inTable 5 below. CHO-Gα16 cells stably expressing FPRL1 were cultured in(F12, 10% FBS, 1% PSA, 400 μg/ml geneticin and 50 μg/ml hygromycin) andHEK-Gqi5 cells stable expressing FPR1 were cultured in (DMEM highglucose, 10% FBS, 1% PSA, 400 μg/ml geneticin and 50 μg/ml hygromycin).In general, the day before the experiment, 18,000 cells/well were platedin a 384-well clear bottom poly-d-lysine coated plate. The following daythe screening compound-induced calcium activity was assayed on theFLIPR^(Tetra). The drug plates were prepared in 384-well microplatesusing the EP3 and the MultiPROBE robotic liquid handling systems.Compounds were tested at concentrations ranging from 0.61 to 10,000 nM.Results are expressed as ECso (nM) and efficacy values.

TABLE 5 FPRL-1 Ga16-CHO IUPAC Name EC₅₀ (nM) Compound (Rel. eff.){[2-{[(4-bromophenyl)carbamoyl]amino}-3-(1H-imidazol- 10.04-yl)propanoyl]amino}acetic acid (0.95) tert-butyl{[2-{[(4-bromophenyl)carbamoyl]amino}-3-(1H- 263imidazol-4-yl)propanoyl]amino}acetate (0.95){[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4- 247(methylsulfonyl)butanoyl]amino}acetic acid (1.01) tert-butyl{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}- 12384-(methylsulfonyl)butanoyl]amino}acetate (0.97){[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4- 7(methylsulfanyl)butanoyl]amino}acetic acid (1.03) tert-butyl{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}- 1274-(methylsulfanyl)butanoyl]amino}acetate (0.98)2-methyl-2-{[(2S)-4-methyl-2-({[4- 2.3(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]ami- (0.92)no}propanoic acid tert-butyl 2-methyl-2-{[(2S)-4-methyl-2-({[4- 1016(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]ami- (1.07)no}propanoate {[(2S)-4-methyl-2-({[4- 459(methylsulfonyl)phenyl]carbamoyl}amino)pentanoyl]ami- (1.12) no}aceticacid tert-butyl {[(2S)-4-methyl-2-({[4- 1083(methylsulfonyl)phenyl]carbamoyl}amino)pentanoyl]ami- (0.90) no}acetate{[(2S)-4-methyl-2-({[4- 358(methylsulfinyl)phenyl]carbamoyl}amino)pentanoyl]ami- (1.21) no}aceticacid tert-butyl {[(2S)-4-methyl-2-({[4- 668(methylsulfinyl)phenyl]carbamoyl}amino)pentanoyl]ami- (0.97) no}acetate2-{[(2S)-2-({[(4-bromophenyl)amino]carbamoyl}amino)- 14-methylpentanoyl] amino}-2-methylpropanoic acid (0.96) tert-butyl2-{[(2S)-2-{[(4- 133 bromophenyl)carbamoyl]amino}-4- (1.16)methylpentanoyl]amino}-2-methylpropanoate ({(2S)-4-methyl-2-[({4- 560[(trifluoromethyl)sulfanyl]phenyl}carbamoyl)ami- (1.07)no]pentanoyl}amino)acetic acid tert-butyl ({(2S)-4-methyl-2-[({4- 3103[(trifluoromethyl)sulfanyl]phenyl}carbamoyl)ami- (0.78)no]pentanoyl}amino)acetate {[(2S)-4-methyl-2-({[4- 2.95(methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]ami- (1.05) no}aceticacid tert-butyl {[(2S)-4-methyl-2-({[4- 116(methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl]ami- (0.98) no}acetate{[(2R)-2-{[(4-bromophenyl)carbamoyl]amino}-4- 1229methylpentanoyl]amino}acetic acid (0.97) tert-butyl{[(2R)-2-{[(4-bromophenyl)carbamoyl]amino}- 36574-methylpentanoyl]amino}acetate (0.92){[(2R,3R)-2-{[(4-bromophenyl)carbamoyl]amino}-3- 19315methylpentanoyl]amino}acetic acid (0.45) tert-butyl {[(2R,3R)-2-{[(4-3974 bromophenyl)carbamoyl]amino}-3- (0.44)methylpentanoyl]amino}acetate {[(2S)-4-methyl-2-({[4- 1.8(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]ami- (0.99) no}aceticacid tert-butyl {[(2S)-4-methyl-2-({[4- 309(trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl]ami- (0.81) no}acetate{[(2R)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4- 1489methylpentanoyl]amino}acetic acid (0.87)(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-[2- 1.4(dimethylamino)-2-oxoethyl]-4-methylpentanamide (0.90)[(2-{[(4-bromophenyl)carbamoyl]amino}-2- 480methylpropanoyl)amino]acetic acid (0.99) tert-butyl[(2-{[(4-bromophenyl)carbamoyl]amino}-2- 114methylpropanoyl)amino]acetate (1.02)[(2-{[(4-bromophenyl)carbamoyl]amino}-2- 19 ethylbutanoyl)amino]aceticacid (1.04) tert-butyl [(2-{[(4-bromophenyl)carbamoyl]amino}-2- 31ethylbutanoyl)amino]acetate (1.03)[(2-{[(4-bromophenyl)carbamoyl]amino}-2,4- 22dimethylpentanoyl)amino]acetic acid (0.98) tert-butyl[(2-{[(4-bromophenyl)carbamoyl]amino}-2,4- 58dimethylpentanoyl)amino]acetate (0.98)(2S)-N-[(1S)-2-amino-2-oxo-1-phenylethyl]-2-{[(4- 84bromophenyl)carbamoyl]amino}-4-methylpentanamide (0.99)(2S)-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4- 9.1methylpentanoyl]amino}(phenyl)ethanoic acid (1.08) tert-butyl(2S)-{[(2S)-2-{[(4- 122 bromophenyl)carbamoyl]amino}-4- (1.02)methylpentanoyl]amino}(phenyl)ethanoate(2S)-N-[(2S)-1-amino-1-oxopentan-2-yl]-2-{[(4- 6.4bromophenyl)carbamoyl]amino}-4-methylpentanamide (1.03)(2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4- 1.0methylpentanoyl]amino}pentanoic acid (0.89) tert-butyl(2S)-2-{[(2S)-2-{[(4- 13 bromophenyl)carbamoyl]amino}-4- (1.06)methylpentanoyl]amino}pentanoate(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-[(2R)-1- 3.0hydroxypropan-2-yl]-4-methylpentanamide (1.00)(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2,3- 5.1dihydroxypropyl)-4-methylpentanamide (0.98)(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(1,3- 7.4dihydroxypropan-2-yl)-4-methylpentanamide (0.96)(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2- 2.1hydroxy-2-methylpropyl)-4-methylpentanamide (1.01)(2S)-N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]-2-{[(4- 1.3bromophenyl)carbamoyl]amino}-4-methylpentanamide (1.03)(2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4- 1.83methylpentanoyl]amino}-3-methylbutanoic acid (1.13) tert-butyl(2S)-2-{[(2S)-2-{[(4- 68 bromophenyl)carbamoyl]amino}-4- (0.98)methylpentanoyl]amino}-3-methylbutanoate(2S)-N-[(2S)-1-amino-1-oxopropan-2-yl]-2-{[(4- 24bromophenyl)carbamoyl]amino}-4-methylpentanamide (0.96)(2S)-2-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4- 11methylpentanoyl]amino}propanoic acid (1.05) tert-butyl(2S)-2-{[(2S)-2-{[(4- 147 bromophenyl)carbamoyl]amino}-4- (0.96)methylpentanoyl]amino}propanoate(2S)-N-[(2S)-1-amino-1-oxopropan-2-yl]-2-{[(4-bromo-2- 31fluorophenyl)carbamoyl]amino}-4-methylpentanamide (1.05)(2S)-2-{[(2S)-2-{[(4-bromo-2- 12 fluorophenyl)carbamoyl]amino}-4- (0.95)methylpentanoyl]amino}propanoic acid tert-butyl(2S)-2-{[(2S)-2-{[(4-bromo-2- 174 fluorophenyl)carbamoyl]amino}-4-(1.00) methylpentanoyl]amino}propanoate(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N- 77(2-hydroxyethyl)-4-methylpentanamide (1.05)(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4- 20methyl-N-(2-oxopropyl)pentanamide (0.99)(2S)-N-(2-amino-2-oxoethyl)-2-{[(4-bromo-2- 4.5fluorophenyl)carbamoyl]amino}-4-methylpentanamide (0.95){[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4- 3.6methylpentanoyl]amino}acetic acid (1.10) tert-butyl{[(2S)-2-{[(4-bromo-2- 134 fluorophenyl)carbamoyl]amino}-4- (1.19)methylpentanoyl]amino}acetate(2S)-N-(2-amino-2-oxoethyl)-2-{[(4-bromo-2- 5.2fluorophenyl)carbamoyl]amino}pentanamide (0.98)(2S)-N-(2-amino-2-oxoethyl)-2-{[(4- 2.5bromophenyl)carbamoyl]amino}pentanamide (0.97)(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methyl-N- 4.7(2-oxopropyl)pentanamide (0.82) (2S)-N-(2-amino-2-oxoethyl)-2-{[(4- 1.05bromophenyl)carbamoyl]amino}-4-methylpentanamide (1.08){[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4- 0.88methylpentanoyl]amino}acetic acid (0.91)(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2- 11hydroxyethyl)-4-methylpentanamide (0.92) tert-butyl{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}- 1404-methylpentanoyl]amino}acetate (0.85) {[(2S)-2-{[(4-bromo-2- 4.8fluorophenyl)carbamoyl]amino}pentanoyl]amino}acetic (0.92) acidtert-butyl {[(2S)-2-{[(4-bromo-2- 83fluorophenyl)carbamoyl]amino}pentanoyl]amino}acetate (0.95)(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N- 92(2-oxopropyl)pentanamide (0.92)(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2- 35 oxopropyl)pentanamide(1.05) propan-2-yl {[(2S)-2-{[(4- 14bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate (1.04) ethyl{[(2S)-2-{[(4- 57 bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate(1.18) methyl {[(2S)-2-{[(4- 17bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate (0.88)(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N- 105(2-hydroxyethyl)pentanamide (0.87)(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2- 38hydroxyethyl)pentanamide (0.92)(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N- 16(2-hydroxyethyl)-3-phenylpropanamide (0.98) {[(2S)-2-{[(4- 3.2bromophenyl)carbamoyl]amino}pentanoyl]amino}acetic (0.91) acidtert-butyl {[(2S)-2-{[(4- 31bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate (0.95)(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-N- 12(2-oxopropyl)-3-phenylpropanamide (0.94)(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2- 29oxopropyl)-3-phenylpropanamide (0.96)(2S,3S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}- 62N-(2-hydroxyethyl)-3-methylpentanamide (1.00)(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2- 24hydroxyethyl)-3-methylpentanamide (1.00)(2S,3S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}- 363-methyl-N-(2-oxopropyl)pentanamide (1.01)(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3- 10methyl-N-(2-oxopropyl)pentanamide (0.97)(2S,3S)-N-(2-amino-2-oxoethyl)-2-{[(4-bromo-2- 10fluorophenyl)carbamoyl]amino}-3-methylpentanamide (1.00)(2S,3S)-N-(2-amino-2-oxoethyl)-2-{[(4- 4.6bromophenyl)carbamoyl]amino}-3-methylpentanamide (0.81){[(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3- 2.7methylpentanoyl]amino}acetic acid (1.00) tert-butyl {[(2S,3S)-2-{[(4-280 bromophenyl)carbamoyl]amino}-3- (0.85) methylpentanoyl]amino}acetate{[(2S,3S)-2-{[(4-bromo-2- 5.5 fluorophenyl)carbamoyl]amino}-3- (0.95)methylpentanoyl]amino}acetic acid tert-butyl {[(2S,3S)-2-{[(4-bromo-2-757 fluorophenyl)carbamoyl]amino}-3- (0.86)methylpentanoyl]amino}acetate(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-N-(2- 6hydroxyethyl)-3-phenylpropanamide (0.92)3-{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-3- 18phenylpropanoyl]amino}propanoic acid (0.98) tert-butyl 3-{[(2S)-2-{[(4-255 bromophenyl)carbamoyl]amino}-3- (1.00)phenylpropanoyl]amino}propanoate{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-3- 7.7phenylpropanoyl]amino}acetic acid (0.99) tert-butyl{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}- 1183-phenylpropanoyl]amino}acetate (0.91) tert-butyl 2-{[(2R)-2-{[(4- 2725bromophenyl)carbamoyl]amino}-4- (0.74)methylpentanoyl]amino}-2-methylpropanoate2-{[(2R)-2-{[(4-bromophenyl)carbamoyl]amino}-4- 490methylpentanoyl]amino}-2-methylpropanoic acid (0.74){[2-{[(4-bromophenyl)carbamoyl]amino}-3-(1H-indol-3- 0.73yl)propanoyl]amino}acetic acid (0.97) tert-butyl{[2-{[(4-bromophenyl)carbamoyl]amino}-3-(1H- 305indol-3-yl)propanoyl]amino}acetate (1.03) [(4-amino-2-{[(4- 2938bromophenyl)carbamoyl]amino}-4- (0.81) oxobutanoyl)amino]acetic acidtert-butyl [(4-amino-2-{[(4- 2306 bromophenyl)carbamoyl]amino}-4- (0.90)oxobutanoyl)amino]acetate

What is claimed is:
 1. A compound selected from the group consisting of:

and pharmaceutically acceptable salts, enantiomers, or diastereoisomersthereof.
 2. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt, enantiomer, or diastereoisomerthereof.
 3. The compound of claim 2, wherein the compound is

or a pharmaceutically acceptable salt, enantiomer, or diastereoisomerthereof.
 4. The compound of claim 2 wherein the compound is

or a pharmaceutically acceptable salt or enantiomer thereof.
 5. Thecompound of claim 2, wherein the compound is

or a pharmaceutically acceptable salt or enantiomer thereof.